Hypothetical bias, cheap talk, and stated willingness to pay for health care.
Subjects with rheumatoid arthritis (RA) enrolled in an online panel were asked to evaluate pairs of treatment alternatives with different attributes. Half of the sample saw a cheap-talk text. Preference parameters were estimated using random-parameters logit models to account for unobserved taste heterogeneity. The models also were estimated in willingness-to-pay (WTP) space instead of conventional utility space. Cheap talk not only affected the coefficient on the cost attribute, but also preferences for other attributes. WTP estimates were generally lower in cheap talk sample, except for the most important attribute and a 2-level attribute. Subjects who were presented with cheap talk discriminated between the adjoning attribute levels better than the subjects in the control sample.


Symptom distress profiles in hospitalized patients in Sweden: a cross-sectional study.
Symptom distress profiles of patients with a variety of diagnoses at two hospitals in Sweden were examined using a point-prevalence cross-sectional survey design. The sample included 710 patients present on internal medicine, surgery, geriatric, and oncology acute care hospital wards of each hospital on a single day. Symptom distress data were collected via structured interviews using a 0-10 numeric rating scale (NRS). Fatigue was the most prevalent symptom, experienced by 76.2% of the patients, followed by pain (65.2%) and sleeping difficulties (52.8%). Symptoms were fairly distressing (median NRS 5-6). Patients experiencing high distress from fatigue and pain were more likely to be female, living alone, and to have more symptoms. Latent class analysis revealed three symptom distress profiles that differed with respect to the degree of distress and number of symptoms. The profiles were not substantially differentiated by diagnoses. Symptom distress needs to be assessed and treated on an individual basis, rather than predicting distress levels based on diagnosis alone.


Mental health outcomes and alcohol consumption among UK military spouses/partners: a comparison with women in the general population.
Background: Military families can experience unique stressors that may contribute towards poorer well-being among the spouses/partners of Service personnel. However, there is little UK research regarding mental health or alcohol consumption among this population. Objective: This study examined mental health outcomes (probable depression and post-traumatic stress disorder (PTSD)) and alcohol consumption among UK military spouses/partners compared to women in the general population. Associations with military and socio-demographic characteristics were examined. Method: Survey data from 405 female spouses/partners of current and former UK Service personnel participating in a study of military-connected children (2010-2012) was analysed. Comparisons to women in the general population were made using the 2007 Adult Psychiatric Morbidity Survey (n = 1594). Results: Compared to women from the general population, military spouses/partners were significantly more likely to meet criteria for probable depression (adj. OR 2.50 (95% CI 1.52-4.11)). There was no significant difference regarding probable PTSD. Spouses/partners were significantly more likely to meet criteria for hazardous alcohol consumption (adj. OR 2.55 (95% CI 1.87-3.47)) and more likely to report episodes of weekly, daily or almost daily binge-drinking (adj. OR 2.15 (95% CI 1.28-3.61)) than women in the general population. Binge-drinking was significantly higher among spouses/partners of Service personnel reporting family separations of more than 2 months in the last 2 years compared to those reporting no, or shorter, separations (adj. OR 1.88 (95% CI 1.08-3.27)). Conclusion: This is the first study to examine mental health and alcohol consumption among UK military spouses/partners. The significantly higher prevalence of probable depression, hazardous alcohol consumption, and binge-drinking compared to women in the general population suggests further research is needed into the drivers of poor mental health and alcohol consumption among this population and in identifying or developing prevention campaigns to reduce alcohol use and support their well-being.


Promotion of the mind through exercise (PROMoTE): a proof-of-concept randomized controlled trial of aerobic exercise training in older adults with vascular cognitive impairment.
Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitive impairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is mounting that exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercise have been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training may be of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitive impairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out a proof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence of efficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mild sub-cortical ischaemic vascular cognitive impairment. A proof-of-concept single-blinded randomized trial comparing a six-month, thrice-weekly, aerobic-based exercise training group with usual care on cognitive and everyday function. Seventy older adults who meet the diagnostic criteria for sub-cortical ischaemic vascular cognitive impairment as outlined by Erkinjuntti and colleagues will be recruited from a memory clinic of a metropolitan hospital. The aerobic-based exercise training will last for 6 months. Participants will be followed for an additional six months after the cessation of exercise training. This research will be an important first step in quantifying the effect of an exercise intervention on cognitive and daily function among seniors with sub-cortical ischaemic vascular cognitive impairment, a recognized risk state for progression to dementia. Exercise has the potential to be an effective, inexpensive, and accessible intervention strategy with minimal adverse effects. Reducing the rate of cognitive decline among seniors with sub-cortical ischaemic vascular cognitive impairment could preserve independent functioning and health related quality of life in this population. This, in turn, could lead to reduced health care resource utilization costs and avoidance of early institutional care.


Induction of a rapid and strong antigen-specific intraepithelial lymphocyte response during oral Encephalitozoon cuniculi infection.
Encephalitozoon cuniculi continues to pose a problem for immunocompromised patients. Previous studies from our laboratory have elucidated the importance of the CD8(+) T cell subset in the protection against systemic parasite infection. There have been no studies related to the mucosal immunity induced against this orally acquired pathogen. In the present study, the immune response generated in the gut after oral E. cuniculi infection was evaluated. An early and rapid increase of the intraepithelial lymphocyte (IEL) population of orally infected animals was observed. This increase in the IEL population started as early as day 3 and peaked at day 7 postinfection with persistent elevation thereafter. At day 7 postinfection, IELs expressed strong cytokine messages (IFN-gamma and IL-10) and were highly cytotoxic for parasite-infected syngeneic macrophages. At an E:T ratio of 80:1, these cells were able to cause >60% Ag-specific target cell lysis. A significant increase in the CD8alphaalpha subset of IEL in response to an oral E. cuniculi infection was observed. To the best of our knowledge, such an early expansion of an IEL population exhibiting strong ex vivo cytotoxicity has not been reported with infectious models. These data suggest that IELs act as important barriers for multiplication of this organism leading to the successful resolution of infection. The protective role of IELs may be due both to their inflammatory (IFN-gamma production and cytotoxic response) as well as immunoregulatory (IL-10 production) properties.


Adhesively bonded Ce:YIG/SOI integrated optical circulator.
A classical 3-port optical circulator is demonstrated on the silicon-on-insulator (SOI) platform. A garnet die with a magneto-optical cerium-doped yttrium iron garnet (Ce:YIG) layer is bonded on top of a Mach-Zehnder interferometer circuit using a thin adhesive bonding layer. The power transmission between different ports is characterized in the presence of an external magnetic field, transversal to the light propagation direction. An isolation of 22 dB is measured at a wavelength of 1562 nm.


Unique structure and dynamics of the EphA5 ligand binding domain mediate its binding specificity as revealed by X-ray crystallography, NMR and MD simulations.
The 16 EphA and EphB receptors represent the largest family of receptor tyrosine kinases, and their interactions with 9 ephrin-A and ephrin-B ligands initiate bidirectional signals controlling many physiological and pathological processes. Most interactions occur between receptor and ephrins of the same class, and only EphA4 can bind all A and B ephrins. To understand the structural and dynamic principles that enable Eph receptors to utilize the same jellyroll β-sandwich fold to bind ephrins, the VAPB-MSP domain, peptides and small molecules, we have used crystallography, NMR and molecular dynamics (MD) simulations to determine the first structure and dynamics of the EphA5 ligand-binding domain (LBD), which only binds ephrin-A ligands. Unexpectedly, despite being unbound, the high affinity ephrin-binding pocket of EphA5 resembles that of other Eph receptors bound to ephrins, with a helical conformation over the J-K loop and an open pocket. The openness of the pocket is further supported by NMR hydrogen/deuterium exchange data and MD simulations. Additionally, the EphA5 LBD undergoes significant picosecond-nanosecond conformational exchanges over the loops, as revealed by NMR and MD simulations, but lacks global conformational exchanges on the microsecond-millisecond time scale. This is markedly different from the EphA4 LBD, which shares 74% sequence identity and 87% homology. Consequently, the unbound EphA5 LBD appears to comprise an ensemble of open conformations that have only small variations over the loops and appear ready to bind ephrin-A ligands. These findings show how two proteins with high sequence homology and structural similarity are still able to achieve distinctive binding specificities through different dynamics, which may represent a general mechanism whereby the same protein fold can serve for different functions. Our findings also suggest that a promising strategy to design agonists/antagonists with high affinity and selectivity might be to target specific dynamic states of the Eph receptor LBDs.


Post-traumatic olfactory dysfunction: a cohort study and update.
Post-traumatic olfactory loss (PTOL) is the third most common aetiology for olfactory disorders. Mechanisms that lead to post-traumatic olfactory disorders include sinonasal affections, damage to the olfactory nerve and lesions of the cerebral olfactory centres. The purpose of this review is to present an update of this condition and to present a cohort study of 90 patients. A review of the literature was made on Medline Pubmed up to May 2009 and a review was also conducted of patients with post-traumatic olfactory loss. The degree of olfactory impairment was related to the severity of head trauma and was particularly frequent in cases of occipital impact. Typically, patients experienced a sudden onset of olfactory symptoms and were more severely affected than in other aetiologies. Results from orthonasal and retronasal testing, chemosensory event-related potentials and olfactory bulb (OB) volume confirmed previous findings: patients are usually anosmic, OB volume correlates with the degree of olfactory loss (better correlation with retronasal scores than with orthonasal scores) and olfactory event-related potentials were recorded in only 18 patients. Accuracy in the evaluation of PTOL patients is based on the expertise and the time spent by the clinician on defining the complaint. Failing treatment, complete evaluation of the PTOL patients may help in counselling for the recovery prognosis, and appropriate counselling must be given to secure the environment and alimentation.


Altered brain network modules induce helplessness in major depressive disorder.
The abnormal brain functional connectivity (FC) has been assumed to be a pathophysiological aspect of major depressive disorder (MDD). However, it is poorly understood, regarding the underlying patterns of global FC network and their relationships with the clinical characteristics of MDD. Resting-state functional magnetic resonance imaging data were acquired from 16 first episode, medication-naïve MDD patients and 16 healthy control subjects. The global FC network was constructed using 90 brain regions. The global topological patterns, e.g., small-worldness and modularity, and their relationships with depressive characteristics were investigated. Furthermore, the participant coefficient and module degree of MDD patients were measured to reflect the regional roles in module network, and the impairment of FC was examined by network based statistic. Small-world property was not altered in MDD. However, MDD patients exhibited 5 atypically reorganized modules compared to the controls. A positive relationship was also found among MDD patients between the intra-module I and helplessness factor evaluated via the Hamilton Depression Scale. Specifically, eight regions exhibited the abnormal participant coefficient or module degree, e.g., left superior orbital frontal cortex and right amygdala. The decreased FC was identified among the sub-network of 24 brain regions, e.g., frontal cortex, supplementary motor area, amygdala, thalamus, and hippocampus. The limited size of MDD samples precluded meaningful study of distinct clinical characteristics in relation to aberrant FC. The results revealed altered patterns of brain module network at the global level in MDD patients, which might contribute to the feelings of helplessness.


Drug diffusivities in nanofibrillar cellulose hydrogel by combined time-resolved Raman and fluorescence spectroscopy.
Hydrogels, natural and synthetic origin, are actively studied for their use for implants and payload carriers. These biomaterials for delivery systems have enormous potential in basic biomedical research, drug development, and long-term delivery of biologics. Nanofibrillated cellulose (NFC) hydrogels, both natural and anionic (ANFC) ones, allow drug loading for immediate and controlled release via the slow drug dissolution of solid drug crystals into hydrogel and its subsequent release. This property makes NFC originated hydrogels an interesting non-toxic and non-human origin material as drug reservoir for long-term controlled release formulation or implant for patient care. A compelling tool for studying NFC hydrogels is Raman spectroscopy, which enables to resolve the chemical structures of different molecules in a high-water content like hydrogels, since Raman spectroscopy is insensitive to water molecules. That offers real time investigation of label-free drugs and their release in high-water-content media. Despite the huge potential of Raman spectroscopy in bio-pharmaceutical applications, the strong fluorescence background of many drug samples masking the faint Raman signal has restricted the widespread use of it. In this study we used a Raman spectrometer capable of suppressing the unpleasant fluorescence background by combining a pulsed laser and time-resolved complementary metal-oxide-semiconductor (CMOS) single-photon avalanche diode (SPAD) line sensor for the label-free investigation of Metronidazole and Vitamin C diffusivities in ANFC. The results show the possibility to modulate the ANFC-based implants and drug delivery systems, when the release rate needs to be set to a desired value. More importantly, the now developed label free real-time method is universal and can be adapted to any hydrogel/drug combination for producing reliable drug diffusion coefficient data in complex and heterogeneous systems, where traditional sampling-based methods are cumbersome to use. The wide temporal range of the time-resolved CMOS SPAD sensors makes it possible to capture also the fluorescence decay of samples, giving rise to a combined time-resolved Raman and fluorescence spectroscopy, which provides additional information on the chemical, functional and structural changes in samples.


Dietary administration of probiotics modulates non-specific immunity and gut microbiota of Nile tilapia (Oreochromis niloticus) cultured in low input ponds.
Poor culture conditions in low input ponds make fish highly susceptible to infectious pathogens which lead to diseases and mortalities yet the effects of probiotics on immunity, gut microbiota and microbiological quality of fish in low input ponds are unknown. Nile tilapia, Oreochromis niloticus fingerlings (40 g) were randomly stocked at 50 fish m-3 in 1.25 m3 cages in low input ponds. The fish were fed on diets supplemented with either Saccharomyces cerevisiae (1 × 1010 CFU g-1) or Bacillus subtilis (1 × 109 CFU g-1) at six levels: Diet 0 (No probiotic); S. cerevisiae at 2 g kg-1 (Diet 1); 4 g kg-1 (Diet 2) and 6 g kg-1 (Diet 3) and B. subtilis at 5 g kg-1 (Diet 4); 10 g kg-1 (Diet 5) and 15 g kg-1 (Diet 6) for 180 days. Results indicate that hemato-immunological parameters (hemoglobin (Hb), red blood cells (RBC), white blood cells (WBC) serum protein, albumin, globulin and lysozyme activity) were significantly higher in fish fed on probiotic treated diets compared to the control (P < 0.05). On the contrary, fish fed on Diet 6 presented significantly similar Hb and globulin values compared to the control (P > 0.05). Additionally, fish fed on probiotic treated diets retained the probiotics in their guts and lower microbial load was realized in their muscle (P < 0.05). In conclusion, B. subtilis and S. cerevisiae supplementation in diets of Nile tilapia reared in low input ponds improves immunity, manipulates gut microbiota and enhances fish flesh quality.


Detailed Characterization of the In Vitro Pharmacological and Pharmacokinetic Properties of N-(2-Hydroxybenzyl)-2,5-Dimethoxy-4-Cyanophenylethylamine (25CN-NBOH), a Highly Selective and Brain-Penetrant 5-HT2A Receptor Agonist.
Therapeutic interest in augmentation of 5-hydroxytryptamine2A (5-HT2A) receptor signaling has been renewed by the effectiveness of psychedelic drugs in the treatment of various psychiatric conditions. In this study, we have further characterized the pharmacological properties of the recently developed 5-HT2 receptor agonist N-2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH) and three structural analogs at recombinant 5-HT2A, 5-HT2B, and 5-HT2C receptors and investigated the pharmacokinetic properties of the compound. 25CN-NBOH displayed robust 5-HT2A selectivity in [3H]ketanserin/[3H]mesulergine, [3H]lysergic acid diethylamide and [3H]Cimbi-36 binding assays (Ki2C/Ki2A ratio range of 52-81; Ki2B/Ki2A ratio of 37). Moreover, in inositol phosphate and intracellular Ca2+ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT2A/5-HT2C selectivities and 54-fold 5-HT2A/5-HT2B selectivity as measured by Δlog(Rmax/EC50) values. In an off-target screening 25CN-NBOH (10 μM) displayed either substantially weaker activity or inactivity at a plethora of other receptors, transporters, and kinases. In a toxicological screening, 25CN-NBOH (100 μM) displayed a benign acute cellular toxicological profile. 25CN-NBOH displayed high in vitro permeability (Papp = 29 × 10-6 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT2A receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor.


Assessing risks to adults and preschool children posed by PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) during a biomass burning episode in Northern Thailand.
To investigate the potential cancer risk resulting from biomass burning, polycyclic aromatic hydrocarbons (PAHs) bound to fine particles (PM2.5) were assessed in nine administrative northern provinces (NNP) of Thailand, before (N-I) and after (N-II) a haze episode. The average values of Σ 3,4-ring PAHs and B[a] P Equivalent concentrations in world urban cities were significantly (p<0.05) much higher than those in samples collected from northern provinces during both sampling periods. Application of diagnostic binary ratios of PAHs underlined the predominant contribution of vehicular exhaust to PM2.5-bound PAH levels in NNP areas, even in the middle of the agricultural waste burning period. The proximity of N-I and N-II values in three-dimensional (3D) principal component analysis (PCA) plots also supports this conclusion. Although the excess cancer risk in NNP areas is much lower than those of other urban area and industrialized cities, there are nevertheless some concerns relating to adverse health impacts on preschool children due to non-dietary exposure to PAHs in home environments.


Spondyloarthritis in a pediatric population: risk factors for sacroiliitis.
Pediatric rheumatologists may have an opportunity to diagnose sacroiliitis in its early stages, prior to the development of irreversible radiographic changes. Early diagnosis frequently requires magnetic resonance imaging (MRI), the use of which is limited by expense and requirement for sedation. We set out to identify features of juvenile spondyloarthritis (SpA) associated with the highest risk of sacroiliitis, to identify patients who may be candidates for routine MRI-based screening. We reviewed the charts of 143 children seen at Texas Scottish Rite Hospital for Children diagnosed with SpA based on the International League of Associations for Rheumatology criteria for enthesitis-related arthritis or the Amor criteria for SpA. We performed logistic regression analysis to identify risk factors for sacroiliitis. A group of 143 children were diagnosed with SpA. Consistent with the diagnosis of SpA, 16% had psoriasis, 43% had enthesitis, 9.8% had acute anterior uveitis, and 70% were HLA-B27+. Fifty-three children had sacroiliitis, of which 11 cases were identified by imaging studies in the absence of suggestive symptoms or physical examination findings. Logistic regression analysis revealed that hip arthritis was a positive predictor of sacroiliitis, while dactylitis was a negative predictor. Children with SpA are at risk for sacroiliitis, which may be present in the absence of suggestive symptoms or physical examination findings. The major risk factor for sacroiliitis is hip arthritis, while dactylitis may be protective. Routine screening by MRI should be considered in patients at high risk of developing sacroiliitis.


Histology and pathology of the human intervertebral disc.
The intervertebral disc is a highly organized matrix laid down by relatively few cells in a specific manner. The central gelatinous nucleus pulposus is contained within the more collagenous anulus fibrosus laterally and the cartilage end plates inferiorly and superiorly. The anulus consists of concentric rings or lamellae, with fibers in the outer lamellae continuing into the longitudinal ligaments and vertebral bodies. This arrangement allows the discs to facilitate movement and flexibility within what would be an otherwise rigid spine. At birth, the human disc has some vascular supply within both the cartilage end plates and the anulus fibrosus, but these vessels soon recede, leaving the disc with little direct blood supply in the healthy adult. With increasing age, water is lost from the matrix, and the proteoglycan content also changes and diminishes. The disc-particularly the nucleus-becomes less gelatinous and more fibrous, and cracks and fissures eventually form. More blood vessels begin to grow into the disc from the outer areas of the anulus. There is an increase in cell proliferation and formation of cell clusters as well as an increase in cell death. The cartilage end plate undergoes thinning, altered cell density, formation of fissures, and sclerosis of the subchondral bone. These changes are similar to those seen in degenerative disc disease, causing discussion as to whether aging and degeneration are separate processes or the same process occurring over a different timescale. Additional disorders involving the intervertebral disc can demonstrate other changes in morphology. Discs from patients with spinal deformities such as scoliosis have ectopic calcification in the cartilage end plate and sometimes in the disc itself. Cells in these discs and cells from patients with spondylolisthesis have been found to have very long cell processes. Cells in herniated discs appear to have a higher degree of cellular senescence than cells in nonherniated discs and produce a greater abundance of matrix metalloproteinases. The role that abnormalities play in the etiopathogenesis of different disorders is not always clear. Disorders may be caused by a genetic predisposition or a tissue response to an insult or altered mechanical environment. Whatever the initial cause, a change in the morphology of the tissue is likely to alter the physiologic and mechanical functioning of the tissue.


Release of antimicrobial compounds from a zinc oxide-chelate cement.
This study examined the release of cetylpyridinium chloride and benzalkonium chloride from fatty acid chelate temporary dental cement and their antimicrobial effects. The cement was Cavex Temporary, and either cetylpyridinium chloride or benzalkonium chloride was added (1% or 5% by mass), incorporating into the base paste. Release of the additives was determined by reverse-phase high-performance liquid chromatography. Possible chemical interactions between the cement components and additives were examined by Fourier transform infrared (FTIR) spectroscopy. Antimicrobial effects were assessed by measuring the zone of inhibition around sample discs after 24 h in a Streptococcus mutans culture. FTIR spectroscopy showed no interaction with cement components. For both additives, release was by diffusion for approximately the first 6 hours, with equilibration after about 2 weeks. Diffusion coefficients were 1.76 m2 s½ to 8.05 × 10-12 m2 s½ and total release was 10.3 to 44.7% of additive loading. Zones of inhibition with additive were significantly larger than those for control discs. In conclusion, the antimicrobial properties of Cavex temporary cement are improved by the addition of the antimicrobial compounds cetylpyridium chloride and benzalkonium chloride, which are released by a diffusion process.


How to use an article about quality improvement.
Quality improvement (QI) attempts to change clinician behavior and, through those changes, lead to improved patient outcomes. The methodological quality of studies evaluating the effectiveness of QI interventions is frequently low. Clinicians and others evaluating QI studies should be aware of the risk of bias, should consider whether the investigators measured appropriate outcomes, should be concerned if there has been no replication of the findings, and should consider the likelihood of success of the QI intervention in their practice setting and the costs and possibility of unintended effects of its implementation. This article complements and enhances existing Users' Guides that address the effects of interventions--Therapy, Harm, Clinical Decision Support Systems, and Summarizing the Evidence guides--with an emphasis on issues specific to QI studies. Given the potential for widespread implementation of QI interventions, there is a need for robust study methods in QI research.


Identification of important regions for ethylene binding and signaling in the transmembrane domain of the ETR1 ethylene receptor of Arabidopsis.
The ethylene binding domain (EBD) of the Arabidopsis thaliana ETR1 receptor is modeled as three membrane-spanning helices. We surveyed ethylene binding activity in different kingdoms and performed a bioinformatic analysis of the EBD. Ethylene binding is confined to land plants, Chara, and a group of cyanobacteria but is largely absent in other organisms, consistent with our finding that EBD-like sequences are overrepresented among plant and cyanobacterial species. We made amino acid substitutions in 37 partially or completely conserved residues of the EBD and assayed their effects on ethylene binding and signaling. Mutations primarily in residues in Helices I and II midregions eliminated ethylene binding and conferred constitutive signaling, consistent with the inverse-agonist model of ethylene receptor signaling and indicating that these residues define the ethylene binding pocket. The largest class of mutations, clustered near the cytoplasmic ends of Helices I and III, gave normal ethylene binding activity yet still conferred constitutive signaling. Therefore, these residues may play a role in turning off the signal transmitter domain of the receptor. By contrast, only two mutations were loss of function with respect to signaling. These findings yield insight into the structure and function of the EBD and suggest a conserved role of the EBD as a negative regulator of the signal transmitter domain.


Altered end-product patterns and catabolite repression in Escherichia coli.
Dobrogosz, Walter J. (North Carolina State University, Raleigh). Altered end-product patterns and catabolite repression in Escherichia coli. J. Bacteriol. 91:2263-2269. 1966.-End products formed during growth of Escherichia coli ML30 on glucose were examined under various conditions known to promote or prevent catabolite repression of the inducible beta-galactosidase system in this organism. Cultures were grown under these conditions in the presence of C(14)-glucose or C(14)-pyruvate. The products formed were assayed isotopically after separation on columns of silicic acid. Under conditions known to promote catabolite repression, glucose was degraded primarily to acetate and CO(2). When repression was turned off by anaerobic shock, glucose metabolism was characterized by the accumulation of ethyl alcohol in addition to acetate and CO(2). The results presented in this report indicate that oxidative decarboxylation of pyruvate may markedly affect the amount of energy that can be derived from glucose catabolism. In turn, the amount of energy derived from catabolic processes may play a key role in the mechanism of catabolite repression.


[Human immunodeficiency virus infection in pregnant women. The importance of recognizing the infection during pregnancy and risk factors for perinatal transmission].
Using adequate infection control measures, the rate of vertical transmission of human immunodeficiency virus (HIV) during pregnancy, has been reduced to 3% in Chile. To determine vertical transmission rate and risk factors associated to perinatal infection in pregnant women with known (KI) and unknown HIV infection (UI). HIV infected pregnant women whose deliveries were attended at the San Borja Arriaran Hospital were included. Antiretroviral therapy (ART) has been used since 1995 (Zidovudine 13 patients, biOtherapy 4 and triple therapy 14 patients). Newborns have received ART since 1995. Premature labor without evident cause, premature rupture of membranes, and rupture of membranes over 4 h before delivery were evaluated. Delivery was by elective cesarean section since 1993. Breast feeding was avoided. Pregnant women with UI (suspected disease after delivery due to child or mother pathology) did not received ART. Delivery and breast feeding were managed with common obstetrical-neonatal criteria. Fifty three HIV infected pregnant women were studied (43 with KI and 10 with UI). Four children (36.4%) from the KI group and seven (63.6%) from the UI group became infected. The global rate of vertical transmission among KI group was significantly lower than UI group: 9.5% (4/42) vs 70.0% (7/10) p < 0.001. Using ART, this rate was further reduced to 6.5% (2/31) and with bitherapy or triple therapy to 0% (0/18). Breast feeding, vaginal delivery, premature delivery with no clinical cause, premature rupture of membranes, rupture of membranes longer than 4 h and lack of ART, were significantly more common in the UI group, compared with KI group. Vertical transmission in pregnant women with KI is significantly lower compared with UI. Risk factors increasing HIV perinatal infection are: breast feeding, lack of ART, vaginal delivery, premature rupture of membranes, rupture of membranes > 4 h and premature labor without a clinical cause.


Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells.
Molecular markers are used to characterize and track adult stem cells. Colon cancer research has led to the identification of 2 related receptors, leucine-rich repeat-containing, G-protein-coupled receptors (Lgr)5 and Lgr6, that are expressed by small populations of cells in a variety of adult organs. Genetic mouse models have allowed the visualization, isolation, and genetic marking of Lgr5(+ve) and Lgr6(+ve) cells and provided evidence that they are stem cells. The Lgr5(+ve) cells were found to occupy locations not commonly associated with stem cells in the stomach, small intestine, colon, and hair follicles. A multipotent population of skin stem cells express Lgr6. Single Lgr5(+ve) stem cells from the small intestine and the stomach can be cultured into long-lived organoids. Further studies of these markers might reveal adult stem cell populations in additional tissues. Identification of the ligands for Lgr5 and 6 will help elucidate stem cell functions and modes of intracellular signaling.


Prevalence of Total and Domain-Specific Physical Activity and Associated Factors Among Nepalese Adults: A Quantile Regression Analysis.
To analyze the data from the World Health Organization Nepal STEPS survey 2013 to determine the prevalence of total and domain-specific physical activity (PA) and associated factors among Nepalese adults. A multistage cluster sampling technique was used to proportionately select participants from the 3 ecological zones (Mountain, Hill, and Terai) in Nepal. The Global PA Questionnaire was used to assess PA. The data were analyzed using quantile and ordinary least square regression. Only 4% of the adults did not meet the World Health Organization PA guidelines. Age had a negative monotonic association with total PA and occupational PA, with the highest difference at the upper tails of the PA distribution. Lower total PA and occupational PA were associated with secondary or higher education, being retired or in unpaid employment, living in Terai or urban areas, and nonsmoking. Age, higher education, unpaid employment, and Terai or urban residence were negatively associated, while being currently married was positively associated with transport-related PA. Increasing age, higher education, unpaid employment, unemployment or retirement, and urban residence were associated with lower PA, with the stronger association at the upper tails of the distribution. The correlates had dissimilar associations across the quantiles of PA distribution.


The teaching of physical assessment skills in pre-registration nursing programmes in Australia: issues for nursing education.
Health assessment is a fundamental aspect of the professional nursing role. The teaching of skills in physical assessment is therefore a large component of pre-registration nursing programmes. As the nursing curriculum becomes more crowded with what is deemed to be essential content, there is a need to rationalise what is taught in preparatory nursing programmes to ensure readiness for practice. The study outlined in this paper, as part of a larger project, explored the teaching of physical assessment skills in pre-registration nursing programmes across Australia. Fifty-three academics completed the 121 item online survey, indicating whether each skill was taught with practice, taught with no practice or not taught at all. The results suggest that only half the skills were being taught by more than 80% of the academics and 23 skills (19%) were taught by more than 90%. Of the 121 skills commonly taught--69 skills (57%) were taught with student practice and 29 (24%) were taught with no student practice. The results of this study raise questions about the teaching of physical assessment in pre-registration nursing programmes. The suggestion is not that skills that are used regularly or infrequently should be removed from the curriculum, rather, the authors propose that consideration be given to whether the teaching of skills that are never likely to be used is occurring at the expense of comprehensive mastery of core skills.


Patient safety regulation in the NHS: mapping the regulatory landscape of healthcare.
The current research project sought to map out the regulatory landscape for patient safety in the English National Health Service (NHS). We used a systematic desk-based search using a variety of sources to identify the total number of organisations with regulatory influence in the NHS; we researched publicly available documents listing external inspection agencies, participated in advisory consultations with NHS regulatory compliance teams and reviewed the websites of all regulatory agencies. Our mapping revealed over 126 organisations who exert some regulatory influence on NHS provider organisations in addition to 211 Clinical Commissioning Groups. The majority of these organisations set standards and collect data from provider organisations and a considerable number carry out investigations. We found a multitude of overlapping functions and activities. The variability in approach and overlapping functions suggest that there is no overall integrated regulatory approach. Regulation potentially provides a variety of benefits in terms of maintaining the safety and quality of care by providing an external perspective on the care being delivered. However, the variability, extent and fragmentation of the regulatory system of the NHS make it hard for regulators to act effectively and places a massive burden on NHS provider organisations. Overlapping regulatory requests may distract locally driven initiatives to improve safety and quality. Further research is needed to understand the full extent of regulatory activity and the true benefits and costs incurred.


Analysis of intrathyroidal cytokine production in thyroid autoimmune disease: thyroid follicular cells produce interleukin-1 alpha and interleukin-6.
Cytokine production was studied in thyroid tissue from patients with Graves' disease, Hashimoto's thyroiditis and non-toxic goitre. The expression of interferon gamma, tumour necrosis factor alpha and beta, interleukin-1 alpha and beta, interleukin-6 and platelet-derived growth factor A chain was assessed by slot-blot analysis of the respective mRNA in freshly isolated tissue samples. All seven cytokines were detected in patients of all groups. Although the respective mRNA levels were, in general, higher in thyroid autoimmune disorders, this appeared to relate to the degree of the lymphocytic infiltration of the thyroid gland at the time of surgery. Purified thyroid follicular cells expressed high levels of interleukin-1 alpha and interleukin-6 mRNA and when established in primary culture, purified thyroid follicular cells from Graves' disease as well as non-toxic goitre produced interleukin-1 alpha and interleukin-6 bioactivity spontaneously. In the case of interleukin-1 this could be further augmented by addition of lipopolysaccharide to the thyroid follicular cell cultures. These results demonstrate that the lymphocytic infiltrate found in autoimmune and non-autoimmune thyroid disorders is associated with cytokine production. Additionally we have shown that intrathyroidal cytokine production is not restricted to thyroid-infiltrating mononuclear cells, but may also involve thyroid follicular cells both in vivo and in vitro. The cytokines produced by thyroid follicular cells may have an important role in stimulating autoantigen specific T cells in vivo as both interleukin-1 and interleukin-6 facilitate T cell activation.


Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.
An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated.


Fractures among patients with dizziness - a ten-year follow-up.
The number of elderly people persons suffering from dizziness is substantial, and dizziness is a risk factor for falls and fractures. Fall-related fractures represent a major public health issue. Longitudinal studies can help find ways of predicting fall-related fractures among frail elderly persons with multisensory dizziness. The aim of the present study was therefore to investigate whether different measures of balance, being male/female or admission to hospital, could predict fracture at a ten-year follow-up in patients suffering from multisensory dizziness. Patients who had participated in two earlier (ten years previous) dizziness studies were sought in the local health authority's patient administrative system. Information was extracted regarding patient hospitalization, for fractures or for any other reason, during the ten-year period. Logistic regression was used to analyse the relations between clinical balance measures, vestibular rehabilitation, admission to hospital, sex, and fracture. There was no difference between the group of patients with fracture and the group of patients without fracture, regarding balance measures at baseline or admission to hospital for reasons other than fracture. There was no difference between men and women in any of the measures. This study did not identify any predictors of fracture. Thus, among frail elderly, attention to fall risk should be equally high regardless of patient history.


The effects of neonatal hypothyroidism on brain catecholamine turnover in adult rats: assessment by a steady-state method.
The effects of hypothyroidism in utero, and continuing into postnatal life, on the central turnover of catecholamines, noradrenaline and dopamine were studied in rats. Rats were rendered hypothyroid in utero by treating pregnant females with methimazole in the drinking water. In two groups goitrogen treatment continued for 3 or 10 weeks postnatally. Methimazole treatment in utero did not produce significant changes in noradrenaline, dopamine or tyrosine content in either the hypothalamus or striatum. Three weeks' postnatal treatment reduced tyrosine specific radioactivity in the anterior hypothalamus and dopamine specific radioactivity in the striatum. Ten weeks' treatment increased dopamine content and reduced noradrenaline synthesis in the mediobasal hypothalamus and a reduction in tyrosine content in the anterior hypothalamus. These data suggest that hypothyroidism restricted to intrauterine life does not produce permanent changes in adult catecholamine neuronal function. Long term hypothyroidism produced localized changes, suggesting a specific rather than general effect.


Microbiologic epidemiology depending on time to occurrence of prosthetic joint infection: a prospective cohort study.
The high microbiologic diversity encountered in prosthetic joint infection (PJI) makes the choice of empirical antimicrobial therapies challenging, especially in cases of implant retention or one-stage exchange. Despite the risk of dysbiosis and toxicity, the combination of vancomycin with a broad-spectrum β-lactam is currently recommended in all cases, even if Gram-negative bacilli (GNB) might be less represented in late PJI. In this context, this study aimed to describe the microbiologic epidemiology of PJI according to the chronology of infection. This prospective cohort study (2011-2016) evaluated the microbiologic aetiology of 567 PJI according to time of occurrence from prosthesis implantation-early (<3 months), delayed (3-12 months) and late (>12 months)-as well as mechanism of acquisition. Initial microbiologic documentation (n = 511; 90.1%) disclosed 164 (28.9%) Staphylococcus aureus (including 26 (16.1%) methicillin-resistant S. aureus), 162 (28.6%) coagulase-negative staphylococci (including 81 (59.1%) methicillin-resistant coagulase-negative staphylococci), 80 (14.1%) Enterobacteriaceae, 74 (13.1%) streptococci and 60 (10.6%) Cutibacterium acnes. Considering nonhaematogenous late PJI (n = 182), Enterobacteriaceae (n = 7; 3.8%) were less represented than in the first year after implantation (n = 56; 17.2%; p <0.001), without difference regarding nonfermenting GNB (4.6% and 2.7%, respectively). The prevalence of anaerobes (n = 40; 21.9%; including 32 (80.0%) C. acnes) was higher in late PJI (p <0.001). Consequently, a broad-spectrum β-lactam might be useful in 12 patients (6.6%) with late PJI only compared to 66 patients (20.3%) with early/delayed PJI (p <0.001). Considering the minority amount of GNB in late postoperative PJI, the empirical use of a broad-spectrum β-lactam should be reconsidered, especially when a two-stage exchange is planned.


Estimating random signal parameters from noisy images with nuisance parameters: linear and scanning-linear methods.
In a pure estimation task, an object of interest is known to be present, and we wish to determine numerical values for parameters that describe the object. This paper compares the theoretical framework, implementation method, and performance of two estimation procedures. We examined the performance of these estimators for tasks such as estimating signal location, signal volume, signal amplitude, or any combination of these parameters. The signal is embedded in a random background to simulate the effect of nuisance parameters. First, we explore the classical Wiener estimator, which operates linearly on the data and minimizes the ensemble mean-squared error. The results of our performance tests indicate that the Wiener estimator can estimate amplitude and shape once a signal has been located, but is fundamentally unable to locate a signal regardless of the quality of the image. Given these new results on the fundamental limitations of Wiener estimation, we extend our methods to include more complex data processing. We introduce and evaluate a scanning-linear estimator that performs impressively for location estimation. The scanning action of the estimator refers to seeking a solution that maximizes a linear metric, thereby requiring a global-extremum search. The linear metric to be optimized can be derived as a special case of maximum a posteriori (MAP) estimation when the likelihood is Gaussian and a slowly varying covariance approximation is made.


Propionibacterium acnes-Derived Extracellular Vesicles Promote Acne-Like Phenotypes in Human Epidermis.
Acne vulgaris is an inflammatory disease occurring in the pilosebaceous unit and is the most common skin condition in young people. A gram-positive bacterium, Propionibacterium acnes, has been suspected to contribute to the development of acne. Here, we report that P. acnes constitutively releases extracellular vesicles (EVs) exhibiting typical EV morphology and size. Moreover, the P. acnes-derived EVs (PEVs) can induce acne-like phenotypes in human epidermal keratinocytes and a reconstituted human skin model. PEVs significantly induced inflammatory cytokines IL-8 and GM-CSF and dysregulated epidermal differentiation by increasing proliferating keratinocytes and decreasing epidermal keratin 10 and desmocollin 1 levels. PEVs showed strong effects, evoking these responses at earlier time points compared with P. acnes extract at the same protein concentration. We verified that PEVs were internalized via clathrin-dependent endocytosis into keratinocytes and that PEV-induced cellular responses occurred via Toll-like receptor 2-dependent signal cascades. Furthermore, PEVs showed a stronger effect than keratinocytes in inducing inflammatory cytokines in myeloid cells. Collectively, our study suggests that PEVs induce acne-like phenotypes in a unique way; therefore, inhibiting the release of EVs from P. acnes or targeting PEV-mediated signaling pathways could represent an alternative method for alleviating acne occurrence and phenotypes.


Remdesivir in Severe COVID-19 and Non-Invasive Ventilation: A Real-Life Experience.
Antiviral treatment is a hot topic regarding therapy for COVID-19. Several antiviral drugs have been tested in the months since the pandemic began. Yet only Remdesivir obtained approval after first trials. The best time to administer Remdesivir is still a matter for discussion and this could also depend upon the severity of lung damage and the staging of the infection. We performed a real-life study of patients hospitalized forCOVID-19 and receiving non-invasive ventilation (NIV). In this single-center study, a 5 day course of Remdesivir was administered as compassionate use. Further therapeutic supports included antibiotics, low molecular weight heparin and steroids. Data collection included clinical signs and symptoms, gas exchange, laboratory markers of inflammation, and radiological findings. Major outcomes were de-escalation of oxygen-support requirements, clinical improvement defined by weaning from ventilation to oxygen therapy or discharge, and mortality. Adverse drug reactions were also recorded. All data were collected during hospitalization and during a 20-day follow up after treatment. 51 patients were enrolled. A global clinical improvement was recorded in 22 patients (43%) at 12 days, and 36 (71%) at 20 days; in particular, at 12 days, 27 patients (53%) also had a de-escalation of oxygen-support class from a therapeutic point of view. Remdesivir use was associated with a lower hazard ratio for clinical improvement in the elderly (older than 70 years) and in subjects with more extensive lung involvement (total severity score at HRCT of more than 14). The 20-day mortality was 13%. Results demonstrated that Remdesivir is associated with an improvement in clinical, laboratory and radiological parameters in patients with severe COVID-19 and showed an overall mortality of 13%. We conclude that, in this cohort, Remdesivir was a beneficial add-on therapy for severe COVID-19, especially in adults with moderate lung involvement at HRCT.


Current patch test results with the European baseline series and extensions to it from the 'European Surveillance System on Contact Allergy' network, 2007-2008.
The pattern of contact sensitization to the supposedly most important allergens assembled in the baseline series differs between countries, presumably at least partly because of exposure differences. Objectives. To describe the prevalence of contact sensitization to allergens tested in consecutive patients in the years 2007 and 2008, and to discuss possible differences. Data from the 39 departments in 11 European countries comprising the European Surveillance System on Contact Allergy network (www.essca-dc.org) in this period have been pooled and analysed according to common standards. Patch test results with the European baseline series, and country-specific or department-specific additions to it, obtained in 25 181 patients, showed marked international variation. Metals and fragrances are still the most frequent allergens across Europe. Some allergens tested nationally may be useful future additions to the European baseline series, for example methylisothiazolinone, whereas a few long-term components of the European baseline series, namely primin and clioquinol, no longer warrant routine testing. The present analysis points to 'excess' prevalences of specific contact sensitization in some countries, although interpretation must be cautious if only few, and possibly specialized, centres are representing one country. A comparison as presented may help to target in-depth research into possible causes of 'excess' exposure, and/or consideration of methodological issues, including modifications to the baseline series.


Genome-Wide Mapping of 5mC and 5hmC Identified Differentially Modified Genomic Regions in Late-Onset Severe Preeclampsia: A Pilot Study.
Preeclampsia (PE) is a leading cause of perinatal morbidity and mortality. However, as a common form of PE, the etiology of late-onset PE is elusive. We analyzed 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in the placentas of late-onset severe PE patients (n = 4) and normal controls (n = 4) using a (hydroxy)methylated DNA immunoprecipitation approach combined with deep sequencing ([h]MeDIP-seq), and the results were verified by (h)MeDIP-qPCR. The most significant differentially methylated regions (DMRs) were verified by MassARRAY EppiTYPER in an enlarged sample size (n = 20). Bioinformatics analysis identified 714 peaks of 5mC that were associated with 403 genes and 119 peaks of 5hmC that were associated with 61 genes, thus showing significant differences between the PE patients and the controls (>2-fold, p<0.05). Further, only one gene, PTPRN2, had both 5mC and 5hmC changes in patients. The ErbB signaling pathway was enriched in those 403 genes that had significantly different 5mC level between the groups. This genome-wide mapping of 5mC and 5hmC in late-onset severe PE and normal controls demonstrates that both 5mC and 5hmC play epigenetic roles in the regulation of the disease, but work independently. We reveal the genome-wide mapping of DNA methylation and DNA hydroxymethylation in late-onset PE placentas for the first time, and the identified ErbB signaling pathway and the gene PTPRN2 may be relevant to the epigenetic pathogenesis of late-onset PE.


The consequences of balanced harvesting of fish communities.
Balanced harvesting, where species or individuals are exploited in accordance with their productivity, has been proposed as a way to minimize the effects of fishing on marine fish communities and ecosystems. This calls for a thorough examination of the consequences balanced harvesting has on fish community structure and yield. We use a size- and trait-based model that resolves individual interactions through competition and predation to compare balanced harvesting with traditional selective harvesting, which protects juvenile fish from fishing. Four different exploitation patterns, generated by combining selective or unselective harvesting with balanced or unbalanced fishing, are compared. We find that unselective balanced fishing, where individuals are exploited in proportion to their productivity, produces a slightly larger total maximum sustainable yield than the other exploitation patterns and, for a given yield, the least change in the relative biomass composition of the fish community. Because fishing reduces competition, predation and cannibalism within the community, the total maximum sustainable yield is achieved at high exploitation rates. The yield from unselective balanced fishing is dominated by small individuals, whereas selective fishing produces a much higher proportion of large individuals in the yield. Although unselective balanced fishing is predicted to produce the highest total maximum sustainable yield and the lowest impact on trophic structure, it is effectively a fishery predominantly targeting small forage fish.


A natural anthocyanin-based multifunctional theranostic agent for dual-modal imaging and photothermal anti-tumor therapy.
Nowadays, cancer is one of the most serious diseases threatening the health of human beings, and imaging-guided photothermal therapy (PTT) is rapidly emerging as a potent oncotherapy strategy due to its unique advantages of high efficiency, noninvasiveness, visualization, and accuracy. In this study, a multifunctional nanoplatform based on gadolinium ion chelated natural anthocyanins (ACNs) is reported, which can be used not only as an excellent photoacoustic/magnetic resonance (PA/MR) dual-modal contrast agent but also for imaging-guided tumor PTT. The nanoparticles obtained have a suitable size, good dispersity, and physiological stability. The excellent biocompatibility and remarkable photothermal effect of the nanoparticles in vitro were demonstrated by CCK-8 assays and co-staining experiments. Moreover, the magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) results obtained in vivo showed that the nanoparticles were ideal dual-modal contrast agents whether given by intravenous or intratumoral injection. After intratumoral injection, the dual-modal PAI/MRI was used for determining the maximum diffusion time of the probe in the tumor site to guide laser treatment, achieving complete tumor elimination without normal tissue injury. Importantly, ACN is a natural compound extracted from black carrots, possessing native biocompatibility and biodegradability, which was further proved by the results of the detailed safety evaluation. Overall, the as-prepared nanoparticles displayed significant tumor diagnosis and treatment effects while mitigating biosafety concerns, and thus this was found to be a promising nanotherapeutic method for cancer treatment.


Occurrence of Parkinson's syndrome in type I Gaucher disease.
Gaucher disease, the most prevalent glycolipid storage disorder, is classically subdivided into types according to the presence or absence of neurological involvement. Type I has hitherto been considered non-neuronopathic. We present six cases and a review of the literature of Parkinsonian symptoms in type I Gaucher disease patients. The hallmark of this atypical Parkinsonian syndrome is a relatively severe clinical course with early appearance of neurological signs in the 4th to 6th decade of life, aggressive progression of the signs and refractoriness to conventional anti-Parkinson therapy. We discuss the implications of these findings in the light of enzyme replacement therapy for Gaucher disease.


Extracellular modulators of Wnt signalling.
Wnt morphogens are secreted signalling proteins that play leading roles in embryogenesis and tissue homeostasis throughout life. Wnt signalling is controlled by multiple mechanisms, including posttranslational modification of Wnts, antagonist binding (to Wnts or their receptors), and regulation of the availability of Wnt receptors. Recent crystallographic, structure-guided biophysical and cell-based studies have advanced our understanding of how Wnt signalling is regulated at the cell surface. Structures include Wnt in complex with the cysteine-rich domain (CRD) of Frizzled, extracellular fragments of Wnt co-receptor LRP6, LRP6-binding antagonists Dickkopf and Sclerostin, antagonists 5T4/WAIF1 and Wnt inhibitory factor 1 (WIF-1), as well as Frizzled-ubiquitin ligases ZNRF3/RNF43 (in isolation and in complexes with Wnt signalling promoters R-spondins and LGR5). We review recent discoveries and remaining questions.


A case series of samar cobra, Naja samarensis Peters, 1861 (Elapidae) envenomation.
The Samar cobra, Naja samarensis Peters, 1861 is one of the World Health Organization's category I venomous snakes in the Philippines. Although N. samarensis is known to inhabit Eastern Visayas, unlike N. philippinensis in Luzon, no clinical case reports have yet been published in the international literature. No immuno-diagnostic assays have been developed for venomous snakes in the Philippines, even for research purposes. Therefore, identification of the causative snake in hospitals is challenging. In vivo pre-clinical tests using mice showed that locally-produced antivenom raised against N. philippinensis venom ["Purified Cobra Antivenom (PCAV)"] cross-neutralised N. samarensis venom. Here, we present five snakebite envenomation cases where causative snakes were confirmed in photos as N. samarensis by an expert local herpetologist. Patients' symptoms and signs varied, from mild to extensive local cytotoxic to systemic neurotoxic envenomation. In one case, venom had been spat into the eye. Out of five patients, two underwent surgical debridement of necrotic tissue at the bite site. One paediatric patient was intubated because of cardiopulmonary arrest. Except for the spitting cobra case, four cases were successfully treated with PCAV and supportive management. These are the first clinical case reports of confirmed N. samarensis envenomation.


Stimulant medication and parent training therapies for attention deficit-hyperactivity disorder.
The present article provides a brief overview of the clinical use of two of the most commonly used and effective therapies for Attention Deficit-Hyperactivity Disorder (ADHD) in children: stimulant medication treatment and training parents in child behavior management skills. The clinical issues involved in the use of each treatment, as well as their limitations, are reviewed, along with evidence for their efficacy. It is concluded that ADHD is a developmental disorder of attention, impulse control, and regulation of activity level that requires multiple treatment methods, which must be applied over long time intervals if they are to produce an impact on the outcome of children with ADHD.


Structural double-mutant cycle analysis of a hydrogen bond network in ketosteroid isomerase from Pseudomonas putida biotype B.
KSI (ketosteroid isomerase) catalyses an allylic isomerization reaction at a diffusion-controlled rate. A hydrogen bond network, Asp(99).Water(504).Tyr(14).Tyr(55).Tyr(30), connects two critical catalytic residues, Tyr(14) and Asp(99), with Tyr(30), Tyr(55) and a water molecule in the highly apolar active site of the Pseudomonas putida KSI. In order to characterize the interactions among these amino acids in the hydrogen bond network of KSI, double-mutant cycle analysis was performed, and the crystal structure of each mutant protein within the cycle was determined respectively to interpret the coupling energy. The DeltaDeltaG(o) values of Y14F/D99L (Tyr(14)-->Phe/Asp(99)-->Leu) KSI, 25.5 kJ/mol for catalysis and 28.9 kJ/mol for stability, were smaller than the sums (i.e. 29.7 kJ/mol for catalysis and 34.3 kJ/mol for stability) for single mutant KSIs respectively, indicating that the effect of the Y14F/D99L mutation was partially additive for both catalysis and stability. The partially additive effect of the Y14F/D99L mutation suggests that Tyr(14) and Asp(99) should interact positively for the stabilization of the transition state during the catalysis. The crystal structure of Y14F/D99L KSI indicated that the Y14F/D99L mutation increased the hydrophobic interaction while disrupting the hydrogen bond network. The DeltaDeltaG(o) values of both Y30F/D99L and Y55F/D99L KSIs for the catalysis and stability were larger than the sum of single mutants, suggesting that either Tyr(30) and Asp(99) or Tyr(55) and Asp(99) should interact negatively for the catalysis and stability. These synergistic effects of both Y30F/D99L and Y55F/D99L mutations resulted from the disruption of the hydrogen bond network. The synergistic effect of the Y55F/D99L mutation was larger than that of the Y30F/D99L mutation, since the former mutation impaired the proper positioning of a critical catalytic residue, Tyr(14), involved in the catalysis of KSI. The present study can provide insight into interpreting the coupling energy measured by double-mutant cycle analysis based on the crystal structures of the wild-type and mutant proteins.


Associations of Objectively Measured Patterns of Sedentary Behavior and Physical Activity with Frailty Status Screened by The Frail Scale in Japanese Community-Dwelling Older Adults.
The objective of this study was to investigate the association between objectively measured patterns of sedentary behavior (SB) and physical activity (PA) and frailty status in Japanese community-dwelling older adults. Data was from 65-75 years older adults from the baseline of Itoshima Frail Study were used. Frailty was assessed using a Japanese version of the FRAIL scale. SB and PA were measured using an accelerometer. Multinomial logistic regression and receiver operating characteristic curve analyses were used to investigate the associations of SB and PA patterns with frailty status. Of the total 819 older adults, half were female (51.8%). The prevalence of robust, pre-frailty and frailty was 60.2%, 27.8%, and 12.0%, respectively. SB variables including total sedentary time, sedentary time in bouts of ≥ 10 min and ≥ 30 min, and mean sedentary bout duration were not associated with frailty status. Except LPA and moderate-to-vigorous physical activity (MVPA) in bouts of < 10 min, PA variables including total MVPA time, MVPA in bouts of ≥ 10 min (bouted MVPA), and steps were significantly associated with lower prevalence of frailty. Area under the curves (AUCs) of total MVPA time, bouted MVPA, and steps were 0.64 (P < 0.001), 0.67 (P < 0.001), and 0.66 (P < 0.001), respectively. The optimal cut-off value of total MVPA time, bouted MVPA, and steps to discriminate between frailty and non-frailty were 43.25 min/day, 9.13 min/day, and 3841 steps/day, respectively. Higher levels of total MVPA time, bouted MVPA, and daily steps were negatively associated with frailty. Lower amounts of bouted MVPA (70 min/week) or steps (4000 steps/day) may be achievable initial targets in older adults for frailty management.


Hemangiopericytoma: long-term outcome revisited. Clinical article.
Hemangiopericytomas are rare tumors that behave aggressively with a high rate of local recurrence and distant metastases. With the aim of determining the outcome and response to various treatment modalities, a series of 39 patients who underwent microsurgical resection for primary meningeal hemangiopericytoma over a 24-year period is presented. Patients with hemangiopericytoma were identified from histopathology records and their medical records were analyzed retrospectively by 2 independent reviewers to collect data on surgical treatment, adjuvant therapy, postoperative course, local or distant recurrence, and follow-up. Of the 39 patients, 19 were male and 20 were female. Mean patient age was 44.1 years. Thirty-four tumors were intracranial and 5 were spinal. The mean follow-up period was 123 months. Twenty-eight patients developed local recurrence. The recurrence rate at 1, 5, and 15 years was 3.5%, 46%, and 92%, respectively. Extraneural metastasis occurred in 8 patients (26%) at an average of 123 months after initial surgery. Recurrences and metastases were treated by surgical excision, external beam radiation therapy (EBRT), chemotherapy, and/or stereotactic radiosurgery. Adjuvant EBRT following initial surgery was found to extend the disease-free interval from 154 months to 254 months, although it did not prevent the development of metastasis. In those patients with EBRT and complete resection, the mean recurrence-free interval was found to be 126.3 months longer (p = 0.04) and overall survival 126 months longer than without EBRT. Furthermore, adjusting for resection, patients undergoing EBRT had 0.33 times increased risk of recurrence compared with those who did not (p = 0.03). A majority of patients remained able to live independently despite revision surgery for recurrence. The mean follow-up of this patient series represents the longest follow-up duration published to date and demonstrates extended survival in a significant number of patients with hemangiopericytoma. Gross-total resection followed by adjuvant EBRT provides patients with the highest probability of an increased recurrence-free interval and overall survival. Prolonged survival justifies long-term follow-up and aggressive treatment of initial, recurrent, and metastatic disease.


Malaria rapid diagnostic tests: Plasmodium falciparum infections with high parasite densities may generate false positive Plasmodium vivax pLDH lines.
Most malaria rapid diagnostic tests (RDTs) detect Plasmodium falciparum and an antigen common to the four species. Plasmodium vivax-specific RDTs target P. vivax-specific parasite lactate dehydrogenase (Pv-pLDH). Previous observations of false positive Pv-pLDH test lines in P. falciparum samples incited to the present study, which assessed P. vivax-specific RDTs for the occurrence of false positive Pv-pLDH lines in P. falciparum samples. Nine P. vivax-specific RDTs were tested with 85 P. falciparum samples of high (>or=2%) parasite density. Mixed P. falciparum/P. vivax infections were ruled out by real-time PCR. The RDTs included two-band (detecting Pv-pLDH), three-band (detecting P. falciparum-antigen and Pv-pLDH) and four-band RDTs (detecting P. falciparum, Pv-pLDH and pan-pLDH). False positive Pv-pLDH lines were observed in 6/9 RDTs (including two- three- and four-band RDTs). They occurred in the individual RDT brands at frequencies ranging from 8.2% to 29.1%. For 19/85 samples, at least two RDT brands generated a false positive Pv-pLDH line. Sixteen of 85 (18.8%) false positive lines were of medium or strong line intensity. There was no significant relation between false positive results and parasite density or geographic origin of the samples. False positive Pv-pLDH lines in P. falciparum samples with high parasite density occurred in 6/9 P. vivax-specific RDTs. This is of concern as P. falciparum and P. vivax are co-circulating in many regions. The diagnosis of life-threatening P. falciparum malaria may be missed (two-band Pv-pLDH RDT), or the patient may be treated incorrectly with primaquine (three- or four-band RDTs).


Scoliosis surgery in patients with adolescent idiopathic scoliosis does not alter lung volume: a 3-dimensional computed tomography-based study.
Retrospective study of surgically treated patients with adolescent idiopathic scoliosis. To determine the change in lung volume after the surgical correction of scoliosis using a volumetric reconstruction of lung volume from computed tomographic (CT) scans. Previously published studies have shown that pulmonary function tests improve after scoliosis correction; however, these results are not consistent. CT-based volumetric studies in patients with scoliosis have previously shown differences in lung volume and lung volume ratio when compared with a normal population. To date, no study exists that analyzes changes in these parameters after scoliosis surgery. A total of 29 patients with adolescent idiopathic scoliosis who had pre- and postoperative CT scans on file were included in this study. Three-dimensional lung volume reconstruction was performed (TeraRecon software, TeraRecon, Inc., Foster City, CA). Appropriate masking methods were used to isolate the lung tissue. Total lung volumes, left and right lung volumes, and left/right lung volume ratio were obtained from the pre- and postoperative CT scans. Hemithoracic symmetry, pre- and postoperative Cobb angle, and kyphosis were also calculated. Neither total lung volume nor left/right lung volume ratio changed significantly postoperatively. Surgery did not significantly change total lung volume (P = 0.87), right lung volume (P = 0.69), left lung volume (P = 0.70), or the ratio between right and left lung volumes (P = 0.87). Hemithoracic asymmetry was significantly improved (P < 0.001). Median preoperative major Cobb angle was 53.2° and median preoperative kyphosis was 32.8°. Postoperatively, the median major Cobb angle was 15.0°, resulting in a 70% Cobb correction, and mean postoperative kyphosis was 31.1°. Corrective scoliosis surgery does not alter total lung volume or the ratio of right-to-left lung volume. Deformity correction leads to an improvement in the symmetry of the thoracic architecture and costovertebral joint mechanics, as evidenced by the improved hemithoracic asymmetry. Thus, the change in pulmonary function tests, which has been previously documented, may be a dynamic rather than a static phenomenon. 4.


Role of cardiac multidetector computed tomography in acute ischemic stroke: a preliminary report.
Cardiac multidetector computed tomography (MDCT) is less dependent upon the patient's condition and may be valuable in the diagnosis of embolic sources when the patient's cooperation is limited due to a neurologic deficit. However, its role has never been validated in acute stroke patients whose stroke mechanism is assumed to be embolic. Consecutive patients who were admitted with acute ischemic stroke from May 1, 2007 to November 30, 2007 were included in this study. Inclusion criteria were (1) any cardiac evidence of high-risk embolic sources for cerebral embolism, or (2) radiological or (3) clinical evidence of embolic stroke. All patients underwent transthoracic echocardiography first, and then cardiac MDCT or transesophageal echocardiography (TEE) was attempted, if possible. The results and feasibility of cardiac MDCT and TEE were compared. One hundred and forty-three patients met the inclusion criteria. Cardiac MDCT was performed in 124 patients (86.7%), TEE in 83 patients (57.3%), whereas 75 patients (52.4%) underwent both studies. Renal insufficiency for cardiac MDCT and lack of cooperation for TEE were found to be the most impeding factors. Among the patients with both evaluations, cardiac MDCT identified a high-risk intracardiac embolic source in 8 and an extracardiac source in 20, while TEE found an intracardiac source in 1 and an extracardiac source in 7. Statistically significant differences were found with respect to detecting cardioembolic sources and high-risk aortic atheroma. Cardiac MDCT is a feasible and accurate diagnostic tool for embolic sources in an acute stroke setting.


The Recovery Process of Postpartum Psychosis from Both the Woman's and Next of Kin's Perspective - An Interview Study in Sweden.
The most serious type of psychiatric disorder in connection with childbirth is postpartum psychosis. With this disorder occasionally follows emotional rejection of the infant which has serious long term effect on mother and child. The aim of this study was to explore the experiences of the recovery process of postpartum psychosis from the women, from the partners of the women, and their next of kin. Interviews were conducted with seven women, who had previously suffered postpartum psychosis, and six of their next of kin. The interviews were transcribed verbatim and analysed using content analysis. TWO CATEGORIES EMERGED: the recovery process and the circumstances of the support provided. The women and their next of kin spoke about the turning point in the illness, their own personal as well as their social recovery, the importance of support not only from relatives and friends, but also from professionals, and the use of medication. However, the key to recovery was an internal decision by the women themselves. Conclusion is that the recovery from this severe mental disorder requires hard work and the key to their recovery was the decision made by the women. This disorder causes a mental darkness to descend, but at the start of the recovery a dim light shines in the dark tunnel. The nursing staff must be made aware that good sleep is important for the psychiatric treatment and that recovery may take a long time. The nurse needs to provide hope and encouragement, as well as help the woman to recognise the strength that exists within her. To reduce the risk of a recurrence of the disorder, the staff needs to offer follow up visits.


Antigen-specific T-cell activation in hyperplastic thymus in myasthenia gravis.
In order to determine whether antigen-specific T-cell activation by dendritic cells (DCs) is accelerated in thymuses exhibiting lymphofollicular hyperplasia (TLFH) among patients with early-onset myasthenia gravis (EOMG), we investigated the expression levels of phosphorylated protein kinase C (PKC)theta and the local relationship between the presence of phosphorylated PKCtheta and the homing receptor CD44 or CD83, a marker for mature DCs, in samples taken from EOMG patients with early improvement following thymectomy, in remnant thymuses from late-onset MG patients, and in non-MG control thymuses. Antigen-specific T-cell activation was markedly accelerated in TLFH from EOMG patients. Activated T cells and adjacent DCs appeared to be components of a CD44(high) cell population circulating from the blood to the thymus. Although there is no convincing evidence that thymectomy is of benefit in MG, in some EOMG patients with early improvement following thymectomy, blockade of CD44-associated circulation mechanisms is probably the cause for the early benefits of thymectomy and is a potential alternative to thymectomy.


Gene Expression and Activity Profiling Reveal a Significant Contribution of Exo-Phosphotransferases to the Extracellular Nucleotides Metabolism in HUVEC Endothelial Cells.
Purinergic signaling maintains local tissue homeostasis in blood vessels via the regulation of vascular tone, blood platelet aggregation, cell proliferation, and differentiation as well as inflammatory responses. Extracellular purines are important signaling molecules in the vasculature, and both purine-hydrolysing as well as -phosphorylating enzymes are considered to selectively govern extracellular nucleotide/nucleoside metabolism. Recent studies have provided some evidence for the existence of these enzymes in a soluble form in human blood and their secretion into the extracellular space under physiological and pathological conditions. However, the comprehensive analysis of endothelium-derived enzymes involved in purine metabolic pathways has received no attention so far. In the presented study, in vitro cultured human umbilical vein endothelial cells (HUVEC) are shown to be an abundant source of exo-nucleotidases comprising 5'-nucleotidase (exo-5'-NT), and nucleoside triphosphate diphosphohydrolases (exo-NTPDase) as well as phosphotransferases, represented by nucleoside diphosphate kinase (exo-NDPK) and adenylate kinase (exo-AK). An attempt is also made to demonstrate that, in contrast to the metabolic pattern determined on the endothelial cell surface, exo-phosphorylating activities markedly predominate over exo-hydrolytic ones. We present for the first time the expression profiles of genes encoding isoenzymes belonging to distinct nucleotide kinase and nucleotidase families. The genes encoding NDPK1, NDPK2, AK1, and AK2 phosphotransferases have been shown to be expressed at the highest level in HUVEC cells. The data indicate the coexistence of secreted and cell-associated factors of endothelial origin mediating ATP-consuming and ATP-generating pathways with the predominance of exo-phosphotransferases activity. The described enzymes contribute to the regulation of purinergic signal duration and extent in the venous vasculature. J. Cell. Biochem. 118: 1341-1348, 2017. © 2016 Wiley Periodicals, Inc.


Thirty-day rehospitalizations among elderly patients with acute myocardial infarction: Impact of postdischarge ambulatory care.
Rehospitalization after acute myocardial infarction (AMI) is common in elderly patients. It increases morbimortality and health care expenditures. The association between ambulatory care after discharge for AMI and rehospitalization has never been studied in France. We analyzed the impact of ambulatory care on rehospitalization of elderly patients (≥65 years) within 30 days after hospital discharge.We conducted a nationwide population-based study of elderly patients hospitalized with a main diagnosis of AMI in France between 2011 and 2013. We excluded patients hospitalized for AMI in the previous year and those who died during the index hospitalization or within 30 days after discharge. The primary outcome was the first all-cause 30-day rehospitalization in an acute care hospital. Individual and neighborhood-level variables were compared among rehospitalized and nonrehospitalized patients. Determinants of 30-day rehospitalization were identified using logistic regression models.Among the 624 eligible patients, 137 (22.0%) were rehospitalized within 30 days after discharge. In multivariate analyses, chronic kidney failure (odds ratio [OR] 1.88; 95% confidence interval [CI], 1.01-3.53) was an independent predictor of 30-day rehospitalization. We found no association among deprivation and spatial accessibility measures and 30-day rehospitalization. The purchase of lipid-lowering drugs prescription within 7 days after discharge was associated with a reduced risk of 30-day rehospitalization (OR 0.53; 95% CI, 0.36-0.79).This study highlights the role of coordination among hospital and primary care physicians in post-AMI discharge and follow-up among elderly patients. Specifically, targeted interventions to reduce 30-day rehospitalizations should focus on patients with comorbidities and use of prescription drugs after hospital discharge.


Intraoperative near-infrared imaging of mesothelioma.
Though difficult to achieve, complete resection of malignant pleural mesothelioma is paramount to improving patient survival. Surgeons have traditionally been limited to using visual inspection and manual palpation to locate and remove cancerous tissue. However, intraoperative molecular imaging (IMI) is a promising new technology in surgery. Molecular imaging utilizes a fluorescent tracer that selectively accumulates in cancer cells. An imaging device is then used to detect and augment the fluorescent signal emitted from the fluorescent cancer cells. Our group and others have demonstrated that molecular imaging with either indocyanine green (ICG) or a folate receptor alpha (FRα) targeted fluorophore can accurately identify a number of intrathoracic malignancies. Early studies of intraoperative imaging have suggested its efficacy for malignant pleural mesothelioma. In a murine model of mesothelioma, intraoperative imaging was found to have sensitivity of 87% and specificity of 83%. In a pilot human study, eight patients with biopsy-proven epithelial malignant pleural mesothelioma were administered 5 mg/kg of intravenous ICG injection 24 h prior to resection. The following day, a near-infrared (NIR) imaging device was used to detect tumor fluorescence intraoperatively. After what was believed to be complete tumor excision, the wound bed was re-imaged for residual fluorescence indicative of retained tumor. When residual fluorescence was detected, additional tissue was resected, if feasible, and specimens were sent for pathologic correlation. In all cases, intraoperative fluorescence localized to mesothelioma deposits which were confirmed on final pathology. Following resection, fluorescence was confirmed ex vivo with a mean tumor-to-background ratio (TBR) of 3.2 (IQR: 2.9-3.4). It is hoped that this technology will improve outcomes for mesothelioma patients by allowing for a more complete oncologic resection.


Neuroprotective actions of methylene blue and its derivatives.
Methylene blue (MB), the first lead chemical structure of phenothiazine and other derivatives, is commonly used in diagnostic procedures and as a treatment for methemoglobinemia. We have previously demonstrated that MB could function as an alternative mitochondrial electron transfer carrier, enhance cellular oxygen consumption, and provide protection in vitro and in rodent models of Parkinson's disease and stroke. In the present study, we investigated the structure-activity relationships of MB in vitro using MB and six structurally related compounds. MB reduces mitochondrial superoxide production via alternative electron transfer that bypasses mitochondrial complexes I-III. MB mitigates reactive free radical production and provides neuroprotection in HT-22 cells against glutamate, IAA and rotenone toxicity. Distinctly, MB provides no protection against direct oxidative stress induced by glucose oxidase. Substitution of a side chain at MB's 10-nitrogen rendered a 1000-fold reduction of the protective potency against glutamate neurototoxicity. Compounds without side chains at positions 3 and 7, chlorophenothiazine and phenothiazine, have distinct redox potentials compared to MB and are incapable of enhancing mitochondrial electron transfer, while obtaining direct antioxidant actions against glutamate, IAA, and rotenone insults. Chlorophenothiazine exhibited direct antioxidant actions in mitochondria lysate assay compared to MB, which required reduction by NADH and mitochondria. MB increased complex IV expression and activity, while 2-chlorphenothiazine had no effect. Our study indicated that MB could attenuate superoxide production by functioning as an alternative mitochondrial electron transfer carrier and as a regenerable anti-oxidant in mitochondria.


HUMN project: detailed description of the scoring criteria for the cytokinesis-block micronucleus assay using isolated human lymphocyte cultures.
Criteria for scoring micronuclei and nucleoplasmic bridges in binucleated cells in the cytokinesis-block micronucleus assay for isolated human lymphocyte cultures are described in detail. Morphological characteristics of mononucleated cells, binucleated cells, and multinucleated cells as well as necrotic and apoptotic cells and nuclear buds are also described. These criteria are illustrated by a series of schematic diagrams as well as a comprehensive set of colour photographs that are of practical assistance during the scoring of slides. These scoring criteria, diagrams and photographs have been used in a HUman MicronNucleus (HUMN) project inter-laboratory slide-scoring exercise to evaluate the extent of variability that can be attributable to individual scorers and individual laboratories when measuring the frequency of micronuclei and nucleoplasmic bridges in binucleated cells as well as the nuclear division index. The results of the latter study are described in an accompanying paper. It is expected that these scoring criteria will assist in the development of a procedure for calibrating scorers and laboratories so that results from different laboratories for the cytokinesis-block micronucleus assay may be more comparable in the future.


Contribution of Human Retroviruses to Disease Development-A Focus on the HIV- and HERV-Cancer Relationships and Treatment Strategies.
Animal retroviruses are known for their transforming potential, and this is also true for the ones hosted by humans, which have gathered expanding attention as one of the potent causative agents in various disease, including specific cancer types. For instance, Human T Lymphotropic virus (HTLV) is a well-studied class of oncoviruses causing T cell leukemia, while human immunodeficiency virus (HIV) leads to acquired immunodeficiency syndrome (AIDS), which is linked to a series of defining cancers including Kaposi sarcoma, certain types of non-Hodgkin lymphoma, and cervical cancer. Of note, in addition to these "modern" exogenous retroviruses, our genome harbors a staggering number of human endogenous retroviruses (HERVs). HERVs are the genetic remnants of ancient retroviral germline infection of human ancestors and are typically silenced in normal tissues due to inactivating mutations and sequence loss. While some HERV elements have been appropriated and contribute to human physiological functions, others can be reactivated through epigenetic dysregulations to express retroviral elements and promote carcinogenesis. Conversely, HERV replication intermediates or protein products can also serve as intrinsic pathogen-associated molecular patterns that cause the immune system to interpret it as an exogenous infection, thereby stimulating immune responses against tumors. As such, HERVs have also been targeted as a potential internal strategy to sensitize tumor cells for promising immunotherapies. In this review, we discuss the dynamic role of human retroviruses in cancer development, focusing on HIV and HERVs contribution. We also describe potential treatment strategies, including immunotherapeutic targeting of HERVs, inhibiting DNA methylation to expose HERV signatures, and the use of antiretroviral drugs against HIV and HERVs, which can be employed as prospective anti-cancer modalities.


Effect of the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) on the incidence of invasive cervical cancer.
The Clinical Laboratory Improvement Act of 1988 (CLIA '88) mandates strict, new quality-control measures for laboratories that interpret cervical cytology smears. Proposed regulations include proficiency testing of cytotechnologists and remediation for technologists and laboratories that fail to meet proposed proficiency standards. Proponents of the new regulations argue that these measures will reduce deaths from cervical cancer by reducing the false-negative rate of the Papanicolaou (Pap) test, but opponents argue that the regulations will increase the price of processing Pap tests and thereby reduce access to cervical cancer screening for high-risk, vulnerable populations. To examine these claims the authors used David Eddy's published simulation to model the natural history and detection of cervical neoplasia, and developed a new model to examine the health consequences of diminished access to Pap testing. The authors estimated the false-negative rate of the Pap test and the price elasticity of demand for preventive services on the basis of the published literature, and modeled the entire range of published or quoted predictions about the impact of CLIA '88 on accuracy and price. The results show that, if effects on access are ignored, reducing the false-negative rate from 15% to 5% would prevent 66 invasive cancers per 100,000 average risk women screened. However, under moderate assumptions regarding the effect of price on access, the regulations would prevent only 11 (instead of 66) cancers per 100,000 eligible women. The regulatory effect is very sensitive to the degree of improvement in the false-negative rate and increase in price that the regulations cause. Over the range of assumptions and predictions encountered in the literature and tested in our analysis, the proposed regulations could greatly reduce or greatly increase the incidence of invasive cancer, especially among high-risk and uninsured women. The implementation of the regulations should be delayed until new information regarding the actual false-negative rate of the Pap test allow a more precise estimate of the potential impact on the incidence of cervical cancer.


Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis.
Transcranial magnetic stimulation (TMS) is a technology that allows for non-invasive modulation of the excitability and function of discrete brain cortical areas. TMS uses alternating magnetic fields to induce electric currents in cortical tissue. In psychiatry, TMS has been studied primarily as a potential treatment for major depression. Most studies indicate that slow-frequency repetitive TMS (rTMS) and higher frequency rTMS have antidepressant properties. A meta-analysis of controlled studies indicates that this effect is fairly robust from a statistical viewpoint. However, effect sizes are heterogeneous, and few studies have shown that rTMS results in substantial rates of clinical response or remission, and the durability of antidepressant effects is largely unknown. We review in detail rTMS studies in the treatment of depression, as well as summarize treatment studies of mania, obsessive-compulsive disorder, post-traumatic stress disorder, and schizophrenia. We also review the application of TMS in the study of the pathophysiology of psychiatric disorders and summarize studies of the safety of TMS in human subjects.


Falls resulting in health care among older people with intellectual disability in comparison with the general population.
Falls are common among older people with intellectual disability (ID) and are also a major contributor to injuries in this population. Yet, fall characteristics have only been sparsely studied, and the results are inconsistent. The aim of the present study was to investigate type of falls, places where they occurred and activities that caused them, as well as health outcomes and health utilisation patterns after falls, among older people with ID in comparison with their age peers in the general population. We established an administrative cohort of people with ID aged 55 years, or more, and alive at the end of 2012 (ID cohort; n = 7936). A cohort from the general population, one-to-one matched by sex and year of birth, was used as referents. Data regarding fall-induced health care episodes in inpatient and outpatient specialist care were collected from the National Patient Register for the period 2002-2012. With the exception of falls from one level to another (i.e. fall on and from stairs and steps, ladder and scaffolding; fall from, out of or through building or structure; fall from tree or cliff and diving or jumping into water; or other fall from one level to another), people in the ID cohort were more likely to fall and fall more often than those in the general population cohort. Falls during a vital activity (e.g. attending to personal hygiene or eating) were twice as common among people with ID compared with the general population. When falling, people with ID were more likely to injure their head and legs but less likely to sustain injuries to the thorax and elbow/forearm. They were more likely to have superficial injuries, open wounds and fractures but less likely to have dislocations, sprain and strains. Fall-related health care visits among people with ID were more likely to be in inpatient care and be unplanned. People with ID were also more likely than those in the general population to have a readmission within 30 days. People with ID are more likely to require specialist care after a fall and also more likely to obtain injuries to the head, compared with the general population. This is important to consider when taking preventive measures to reduce falls and fall-related injuries.


Whey protein effects on energy balance link the intestinal mechanisms of energy absorption with adiposity and hypothalamic neuropeptide gene expression.
We tested the hypothesis that dietary whey protein isolate (WPI) affects the intestinal mechanisms related to energy absorption and that the resulting energy deficit is compensated by changes in energy balance to support growth. C57BL/6 mice were provided a diet enriched with WPI with varied sucrose content, and the impact on energy balance-related parameters was investigated. As part of a high-sucrose diet, WPI reduced the hypothalamic expression of pro-opiomelanocortin gene expression and increased energy intake. The energy expenditure was unaffected, but epididymal weight was reduced, indicating an energy loss. Notably, there was a reduction in the ileum gene expression for amino acid transporter SLC6a19, glucose transporter 2, and fatty acid transporter 4. The composition of the gut microbiota also changed, where Firmicutes were reduced. The above changes indicated reduced energy absorption through the intestine. We propose that this mobilized energy in the adipose tissue and caused hypothalamic changes that increased energy intake, acting to counteract the energy deficit arising in the intestine. Lowering the sucrose content in the WPI diet increased energy expenditure. This further reduced epididymal weight and plasma leptin, whereupon hypothalamic ghrelin gene expression and the intestinal weight were both increased. These data suggest that when the intestine-adipose-hypothalamic pathway is subjected to an additional energy loss (now in the adipose tissue), compensatory changes attempt to assimilate more energy. Notably, WPI and sucrose content interact to enable the component mechanisms of this pathway.