Managing the severely proclined maxillary anteriors by extracting traumatized right maxillary central incisor.
A 14-year-old girl reported with severely proclined maxillary anterior teeth with fractured and discolored right maxillary central incisor with questionable prognosis. Autotransplantation of premolar to replace central incisor was considered a risky option as patient was 14-year-old with presence of advanced root development of premolar. The immediate placement of the prosthetic implant was also not possible because of patient's age. Therefore, it was decided to use the space obtained by extracting questionable maxillary right central incisor for orthodontic purpose and also sacrificing the healthy premolar is invariably an excessive biological cost for a modest functional and aesthetic gain. Hence, the treatment plan for this case includes extraction of right maxillary central incisor and left maxillary first premolar, movement of right maxillary lateral incisor mesially, achieving normal axial inclination of maxillary anteriors with normal overjet and overbite. Mandibular arch was treated nonextraction due to congenitally missing central incisors with presence of normally inclined lower anteriors thereby maintaining Angles class I occlusion. Tipping, usually, seen in Begg mechanotherapy was used for our advantage to correct severely proclined maxillary anteriors with simultaneous bite opening mechanics. Case was completed in 19 months and posttreatment records including photographs, radiographs and study models were made. Begg wrap around the retainer was placed in the maxillary arch allowing natural settling of occlusion.


Traumatic brain injury in the Netherlands: incidence, costs and disability-adjusted life years.
Traumatic brain injury (TBI) is a major cause of death and disability, leading to great personal suffering and huge costs to society. Integrated knowledge on epidemiology, economic consequences and disease burden of TBI is scarce but essential for optimizing healthcare policy and preventing TBI. This study aimed to estimate incidence, cost-of-illness and disability-adjusted life years (DALYs) of TBI in the Netherlands. This study included data on all TBI patients who were treated at an Emergency Department (ED - National Injury Surveillance System), hospitalized (National Medical Registration), or died due to their injuries in the Netherlands between 2010-2012. Direct healthcare costs and indirect costs were determined using the incidence-based Dutch Burden of Injury Model. Disease burden was assessed by calculating years of life lost (YLL) owing to premature death, years lived with disability (YLD) and DALYs. Incidence, costs and disease burden were stratified by age and gender. TBI incidence was 213.6 per 100,000 person years. Total costs were €314.6 (USD $433.8) million per year and disease burden resulted in 171,200 DALYs (on average 7.1 DALYs per case). Men had highest mean costs per case (€19,540 versus €14,940), driven by indirect costs. 0-24-year-olds had high incidence and disease burden but low economic costs, whereas 25-64-year-olds had relatively low incidence but high economic costs. Patients aged 65+ had highest incidence, leading to considerable direct healthcare costs. 0-24-year-olds, men aged 25-64 years, traffic injury victims (especially bicyclists) and home and leisure injury victims (especially 0-5-year-old and elderly fallers) are identified as risk groups in TBI. The economic and health consequences of TBI are substantial. The integrated approach of assessing incidence, costs and disease burden enables detection of important risk groups in TBI, development of prevention programs that target these risk groups and assessment of the benefits of these programs.


Liquid crystal assisted optical fibres.
Microstructured fibres which consist of a circular step index core and a liquid crystal inclusion running parallel to this core are investigated. The attenuation and electro-optic effects of light coupled into the core are measured. Coupled mode theory is used to study the interaction of core modes with the liquid crystal inclusion. The experimental and theoretical results show that these fibres can exhibit attenuation below 0.16 dB cm(-1) in off-resonant wavelength regions and still have significant electro-optic effects which can lead to a polarisation extinction of 6 dB cm(-1).


Structure of catalase-A from Saccharomyces cerevisiae.
The structure of the peroxisomal catalase A from the budding yeast Saccharomyces cerevisiae, with 515 residues per subunit, has been determined and refined to 2.4 A resolution. The crystallographic agreement factors R and Rfree are 15.4% and 19.8%, respectively. A tetramer with accurate 222-molecular symmetry is located in the asymmetric unit of the crystal. The conformation of the central core of catalase A, about 300 residues, remains similar to the structure of catalases from distantly related organisms. In contrast, catalase A lacks a carboxy-terminal domain equivalent to that found in catalase from Penicillium vitalae, the only other fungal catalase structure available. Structural peculiarities related with the heme and NADP(H) binding pockets can be correlated with biochemical characteristics of the catalase A enzyme. The network of molecular cavities and channels, filled with solvent molecules, supports the existence of one major substrate entry and at least two possible alternative pathways to the heme active site. The structure of the variant protein Val111Ala, also determined by X-ray crystallography at 2.8 A resolution, shows a few, well-localized, differences with respect to the wild-type enzyme. These differences, that include the widening of the entry channel in its narrowest point, provide an explanation for both the increased peroxidatic activity and the reduced catalatic activity of this mutant.


Experimental realization of a polarization-independent ultraviolet/visible coaxial plasmonic metamaterial.
We report the experimental realization of an optical metamaterial composed of a hexagonal array of coaxial plasmonic metal/insulator/metal waveguides that shows strong polarization-independent optical mode index dispersion in the ultraviolet/blue. The metamaterial is composed of silicon coaxes with a well-defined diameter in the range of 150-168 nm with extremely thin sidewalls (13-15 nm), embedded in a silver film, fabricated using a combination of electron beam lithography, physical vapor deposition, reactive ion etching, and focused ion beam polishing. Using a Mach-Zehnder interferometer the phase advance is measured on several metamaterial samples with different dimensions in the UV/visible part of the spectrum. For all geometries the spectral features as well as the geometry dependence of the data correspond well with numerical finite-difference time domain simulations and the calculated waveguide dispersion diagram, showing a negative mode index between 440 and 500 nm.


Separable learning systems in the macaque brain and the role of orbitofrontal cortex in contingent learning.
Orbitofrontal cortex (OFC) is widely held to be critical for flexibility in decision-making when established choice values change. OFC's role in such decision making was investigated in macaques performing dynamically changing three-armed bandit tasks. After selective OFC lesions, animals were impaired at discovering the identity of the highest value stimulus following reversals. However, this was not caused either by diminished behavioral flexibility or by insensitivity to reinforcement changes, but instead by paradoxical increases in switching between all stimuli. This pattern of choice behavior could be explained by a causal role for OFC in appropriate contingent learning, the process by which causal responsibility for a particular reward is assigned to a particular choice. After OFC lesions, animals' choice behavior no longer reflected the history of precise conjoint relationships between particular choices and particular rewards. Nonetheless, OFC-lesioned animals could still approximate choice-outcome associations using a recency-weighted history of choices and rewards.


Reversal of severe cognitive impairment following medical treatment of cystic invasive giant prolactinoma.
Giant prolactinomas are rare tumours of the pituitary, which typically exceed 40 mm in their largest dimension. Impairment of higher cognitive function has been noted post-operatively after transcranial surgery and as a long-term consequence of the radiotherapy treatment. However, there has been little that is reported on such disturbances in relation to the tumour per se, and to our knowledge, there has been none in terms of responsivity to dopamine agonist therapy and shrinkage in these tumours. We present a case of successful restoration of severely impaired cognitive functions achieved safely after significant adenoma involution with medical treatment alone. Giant prolactinomas can be present with profound cognitive defects.Dopamine agonists remain in the mainstay first-line treatment of giant prolactinomas.Mechanisms of the reversible cognitive impairment associated with giant prolactinoma treatment appear to be complex and remain open to further studies.Young patients with giant prolactinomas mandate genetic testing towards familial predisposition.


Vitamins B2 and B6 and genetic polymorphisms related to one-carbon metabolism as risk factors for gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.
B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P(trend)) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93, <0.01) for vitamin B6. Both relations were stronger in individuals with severe chronic atrophic gastritis. The polymorphisms were not associated with GC risk and did not modify the observed vitamin-cancer associations. In summary, results from this large European cohort study showed an inverse association between vitamin B2 and GC risk, which is borderline significant, and a significant inverse association between vitamin B6 and GC risk.


Cardiac abnormalities in stroke patients with negative arteriograms.
Sixty-five consecutive patients with recent unequivocal TIA (33) or stroke (32), but nondiagnostic arteriograms, had two-dimensional echocardiograms (2DE) and electrocardiograms (ECG) to determine the incidence of cardiac abnormalities which could cause embolic stroke. Abnormalities were classified according to increasing probability of causing an embolic event: non-specific, possible emboligenic abnormality (PEA) or definite emboligenic abnormality (EA). Although 2DE was abnormal in 33 patients (51%), and ECG in 38 (59%), many abnormalities were nonspecific. Only four patients (6%) had EA on ECG and two (3%) on 2DE. Since one patient had EA on both tests, 2DE identified only one patient (mitral valve prolapse) not already identified by ECG. All patients with EA had a prior history of cardiac disease. PEA was present on ECG in 11 patients (17%), and on 2DE in 25 (38%). There was no correlation between age, CT results, or neurologic symptoms commonly associated with embolic stroke and the presence of EA or PEA on ECG or 2DE. Although TIA and stroke patients with negative arteriograms have a high incidence of abnormalities on ECG and 2DE, the percentage of patients with EA is low, and cardiac history and ECG identify most patients. 2DE provides little additional information.


The Use of Haddon's Matrix to Plan for Injury and Illness Prevention at Outdoor Music Festivals.
Mass-gathering music events, such as outdoor music festivals (OMFs), increase the risk of injuries and illnesses among attendees. This increased risk is associated with access to alcohol and other drugs by young people and an environment that places many people in close contact with each other. The purpose of this report was to demonstrate how Haddon's matrix was used to examine the factors that contributed to injuries and illnesses that occurred at 26 OMFs using data from the Ranse and Hutton's minimum data set. To help understand the kinds of injuries and illnesses experienced, Hutton et al identified previous patterns of patient presentations at 26 OMFs in Australia. To develop effective prevention strategies, the next logical step was to examine the risk factors associated with each illness/injury event. The Haddon matrix allows event practitioners to formulate anticipatory planning for celebratory-type events. What was evident from this work was that the host, the agent, and the physical and social environments contributed to the development of injuries and illness at an event. The physical environment could be controlled, to a certain extent, through event design, safety guidelines, and legislation. However, balancing cultural norms, such as the importance placed on celebratory events, with the social environment is more difficult. The use of the Haddon matrix demonstrates that interventions need to be targeted at all stages of the event, particularly both pre-event and during the event. The opportunity to promote health is lost by the time of post event. The matrix provided vital information on what factors may contribute to injury at OMFs; form this information, event planners can strategize possible interventions.


Misracialization of Indigenous People in Population Health and Mortality Studies: A Scoping Review to Establish Promising Practices.
Indigenous people are often misracialized or misclassified as other racial or ethnic identities in population health research. This misclassification leads to underestimation of Indigenous-specific mortality and health metrics, and subsequently, inadequate resource allocation. In recognition of this problem, investigators around the world have devised analytic methods to address racial misclassification of Indigenous people. We carried out a scoping review based on searches in PubMed, Web of Science, and the Native Health Database for empirical studies published after 2000 that include Indigenous-specific estimates of health or mortality and that take analytic steps to rectify racial misclassification of Indigenous people. We then considered the weaknesses and strengths of implemented analytic approaches, with a focus on methods used in the United States (U.S.) context. To do this, we extracted information from 97 articles and compared the analytic approaches used. The most common approach to address Indigenous misclassification is to use data linkage, though other methods include geographic restriction to areas where misclassification is less common, exclusion of some subgroups, imputation, aggregation, and electronic health record abstraction. We identified four primary limitations of these approaches: (1) combining data sources that use inconsistent process and/or sources of race and ethnicity information, (2) conflating race, ethnicity, and nationality, (3) applying insufficient algorithms to bridge, impute, or link race and ethnicity information, and (4) assuming the hyperlocality of Indigenous people. While there is no perfect solution to the issue of Indigenous misclassification in population-based studies, a review of this literature provided promising practices to consider.


How important is the back reaction of electrons via the substrate in dye-sensitized nanocrystalline solar cells?
The role of the conducting glass substrate (fluorine-doped tin oxide, FTO) in the back reaction of electrons with tri-iodide ions in dye-sensitized nanocrystalline solar cells (DSCs) has been investigated using thin-layer electrochemical cells that are analogues of the DSCs. The rate of back reaction is dependent on the type of FTO and the thermal treatment. The results show that this back-reaction route cannot be neglected in DSCs, particularly at lower light intensities, where it is the dominant route for the back transfer of electrons to tri-iodide. This conclusion is confirmed by measurements of the intensity dependence of the photovoltages of DSCs with and without blocking layers. It follows that blocking layers should be used to prevent the back reaction in mechanistic studies in which the light intensity is varied over a wide range. Conclusions based on studies of the intensity dependence of the parameters of DSCs such as photovoltage and electron lifetime in cells without blocking layers, must be critically re-examined.


Epidemiology of injury and illness in 153 Australian international-level rowers over eight international seasons.
To report the epidemiology of injury and illness in elite rowers over eight seasons (two Olympiads). All athletes selected to the Australian Rowing Team between 2009 and 2016 were monitored prospectively under surveillance for injury and illness. The incidence and burden of injury and illness were calculated per 1000 athlete days (ADs). The body area, mechanism and type of all injuries were recorded and followed until the resumption of full training. We used interrupted time series analyses to examine the association between fixed and dynamic ergometer testing on rowers' injury rates. Time lost from illness was also recorded. All 153 rowers selected over eight seasons were observed for 48 611 AD. 270 injuries occurred with an incidence of 4.1-6.4 injuries per 1000 AD. Training days lost totalled 4522 (9.2% AD). The most frequent area injured was the lumbar region (84 cases, 1.7% AD) but the greatest burden was from chest wall injuries (64 cases, 2.6% AD.) Overuse injuries (n=224, 83%) were more frequent than acute injuries (n=42, 15%). The most common activity at the time of injury was on-water rowing training (n=191, 68). Female rowers were at 1.4 times the relative risk of chest wall injuries than male rowers; they had half the relative risk of lumbar injuries of male rowers. The implementation of a dynamic ergometers testing policy (Concept II on sliders) was positively associated with a lower incidence and burden of low back injury compared with fixed ergometers (Concept II). Illness accounted for the greatest number of case presentations (128, 32.2% cases, 1.2% AD). Chest wall and lumbar injuries caused training time loss. Policy decisions regarding ergometer testing modality were associated with lumbar injury rates. As in many sports, illness burden has been under-recognised in elite Australian rowers.


Laparoscopically implanted tissue expander radiotherapy in canine transitional cell carcinoma.
Organ motion and injury to adjacent structures limit curative treatment of intraabdominal tumors with external beam radiotherapy. We evaluated the use of Laparoscopically Implanted Tissue Expander Radiotherapy (LITE-RT) to exclude critical structures during irradiation of the urinary bladder in two dogs with transitional cell carcinoma (TCC) using helical tomotherapy. Dogs had histologically confirmed bladder TCC with no metastasis. A custom-shaped tissue expander was placed between the colon and bladder laparoscopically in one dog and during laparotomy in the other. The prescribed radiation dose was 45 Gy to 98% volume of the bladder in 18 fractions of 2.5 Gy. Tumor response and normal tissue effects were monitored with cystoscopy and colonic biopsies before treatment and 3, 6, and 15 months after treatment. Based on treatment plans from inflated vs. deflated tissue expander CT images, there was a mean dose reduction to the colon of 53% and 31% for the two dogs. Interfractional target repositioning was possible by using volumetric megavoltage computed tomography helical tomotherapy. Both dogs had no clinical signs of chronic colitis but did experience mild cystitis during treatment. Tissue expanders became detached, requiring an additional surgery for reattachment, in both dogs. One dog developed a fibrous adhesion resulting in bladder rupture during inflation, which necessitated early device removal. One dog was euthanized for tumor-associated ureteral obstruction at 8 months while the other is alive at 21 months. We conclude that LITE-RT shows promise in treatment of canine bladder TCC due to lack of acute colitis and enteritis.


NaRALF, a peptide signal essential for the regulation of root hair tip apoplastic pH in Nicotiana attenuata, is required for root hair development and plant growth in native soils.
Rapid alkalinization factor (RALF) is a 49-amino-acid peptide that rapidly alkalinizes cultivated tobacco cell cultures. In the native tobacco Nicotiana attenuata, NaRALF occurs as a single-copy gene and is highly expressed in roots and petioles. Silencing the NaRALF transcript by transforming N. attenuata with an inverted-repeat construct generated plants (irRALF) with normal wild-type (WT) above-ground parts, but with roots that grew longer and produced trichoblasts that developed into abnormal root hairs. Most trichoblasts produced a localized 'bulge' without commencing root hair tip growth; fewer trichoblasts grew, but were only 10% as long as those of WT plants. The root hair phenotype was associated with slowed apoplastic pH oscillations, increased pH at the tips of trichoblasts and decreased accumulation of reactive oxygen species in the root hair initiation zone. The root hair growth phenotype was partially restored when irRALF lines were grown in a low-pH-buffered medium, and reproduced in WT plants grown in a high-pH-buffered medium. When irRALF plants were grown in pH 5.6, 6.7 and 8.1 soils together with WT plants in glasshouse experiments, they were out-competed by WT plants in basic, but not acidic, soils. When WT and irRALF lines were planted into the basic soils of the native habitat of N. attenuata in the Great Basin Desert, irRALF plants had smaller leaves, shorter stalks, and produced fewer flowers and seed capsules than did WT plants. We conclude that NaRALF is required for regulating root hair extracellular pH, the transition from root hair initiation to tip growth and plant growth in basic soils.


Parkinson's Disease Genetic Loci in Rapid Eye Movement Sleep Behavior Disorder.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.


Synthesis of the ABCDEFG ring system of maitotoxin.
Maitotoxin (1) continues to fascinate scientists not only because of its size and potent neurotoxicity but also due to its molecular architecture. To provide further support for its structure and facilitate fragment-based biological studies, we developed an efficient chemical synthesis of the ABCDEFG segment 3 of maitotoxin. (13)C NMR chemical shift comparisons of synthetic 3 with the corresponding values for the same carbons of maitotoxin revealed a close match, providing compelling evidence for the correctness of the originally assigned structure to this polycyclic system of the natural product. The synthetic strategy for the synthesis of 3 relied heavily on our previously developed furan-based technology involving sequential Noyori asymmetric reduction and Achmatowicz rearrangement for the construction of the required tetrahydropyran building blocks, and employed a B-alkyl Suzuki coupling and a Horner-Wadsworth-Emmons olefination to accomplish their assembly and elaboration to the final target molecule.


Generation of Polar Semi-Saturated Bicyclic Pyrazoles for Fragment-Based Drug-Discovery Campaigns.
Synthesising polar semi-saturated bicyclic heterocycles can lead to better starting points for fragment-based drug discovery (FBDD) programs. We report the application of diverse chemistry to construct bicyclic systems from a common intermediate, where pyrazole, a privileged heteroaromatic able to bind effectively to biological targets, is fused to diverse saturated counterparts. The generated fragments can be further developed either after confirmation of their binding pose or early in the process, as their synthetic intermediates. Essential quality control (QC) for selection of small molecules to add to a fragment library is discussed.


Long-term developmental outcomes in patients with deformational plagiocephaly.
To determine whether there was an increased rate of later developmental delay in school-aged children who presented as infants with deformational plagiocephaly without obvious signs of delay at the time of initial evaluation. A retrospective medical record review of 254 patients evaluated at the Craniofacial Center of the Children's Hospital and Regional Medical Center in Seattle, Washington, from 1980 through 1991 was completed. Consenting patient families were interviewed via telephone to determine what, if any, special medical or educational problems had occurred for the children who had had plagiocephaly in infancy or their siblings with normal head shapes. A total of 181 families from the medical record review could be notified about the study and 63 families agreed to participate in a telephone interview. The sample of participants for the telephone interview was random to and representative of the group as a whole. The families reported that 25 of the 63 children (39.7%) with persistent deformational plagiocephaly had received special help in primary school including: special education assistance, physical therapy, occupational therapy, speech therapy generally through an Individual Education Plan. Only 7 of 91 siblings (7.7%), serving as controls, required similar services (chi(2) = 21.24). Delays could not be specifically anticipated at the time of the diagnosis of deformational plagiocephaly from any simple set of factors including treatment with helmet therapy, although effected males with reported uterine constraint were at the highest risk for subsequent school problems. Infants with deformational plagiocephaly comprise a high-risk group for developmental difficulties presenting as subtle problems of cerebral dysfunction during the school-age years. There is a need for additional research on the long-term developmental problems in infants with deformational plagiocephaly. plagiocephaly, facial asymmetry, torticollis, developmental delay.


Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors or thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial.
This study sought to evaluate the relative safety and efficacy of fondaparinux and enoxaparin in patients with acute coronary syndromes (ACS) treated with glycoprotein (GP) IIb/IIIa inhibitors or thienopyridines. The OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial showed that fondaparinux reduced major bleeding by 50% compared with enoxaparin while preserving similar efficacy. Whether this benefit is consistent in the presence or absence of concurrent antiplatelet therapy with clopidogrel and GP IIb/IIIa inhibitors is unknown. Patients with ACS (n = 20,078) were randomized as a part of the OASIS 5 trial to receive either fondaparinux or enoxaparin. The use of GP IIb/IIIa inhibitors or thienopyridines was at the discretion of the treating physician. A Cox proportional hazard model was used to compare outcomes. Of the 20,078 patients randomized, 3,630 patients received GP IIb/IIIa and 13,531 received thienopyridines. There was a 40% reduction in major bleeding with fondaparinux compared with enoxaparin in those treated with GP IIb/IIIa (5.2% vs. 8.3%, hazard ratio [HR]: 0.61, p < 0.001). A similar reduction was found in those treated with thienopyridines (3.4% vs. 5.4%, HR: 0.62, p < 0.001). Ischemic events were similar between the groups, resulting in a superior net clinical outcome (death, myocardial infarction, refractory ischemia, or major bleeding) favoring fondaparinux (GP IIb/IIIa subgroup 14.8% vs. 18.9%, HR: 0.77, p = 0.001 and thienopyridines subgroup 11.0% vs. 13.2%, HR: 0.82, p < 0.001). In patients receiving GP IIb/IIIa inhibitors or thienopyridines, fondaparinux reduces major bleeding and improves net clinical outcome compared with enoxaparin.


Blood pressure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
In September 2017, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference titled Blood Pressure in Chronic Kidney Disease (CKD). The purpose of the meeting was to consider which recommendations from the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD should be reevaluated based on new evidence from clinical trials. Participants included a multidisciplinary panel of clinical and scientific experts. Discussions focused on the optimal means for measuring blood pressure (BP) as well as managing BP in CKD patients. Consistent with the 2012 Guideline, the conference did not address BP management in patients on maintenance dialysis.


Systemic sporotrichosis: pulmonary complications of a well-known cutaneous fungal disease. A case report.
Pulmonary involvement during Sporotrichium schenkii infection can present as either primary pulmonary or systemic disease. The clinical and radiological features in the primary form closely resemble those of adult-type tuberculosis. On clinical, radiological and histopathological grounds pulmonary involvement during systemic spread can be difficult to distinguish from sarcoidosis. The diagnostic and therapeutic problems encountered in a woman with systemic sporotrichosis infection with pulmonary involvement are described.


S-nitrosoglutathione acts as a small molecule modulator of human fibrin clot architecture.
Altered fibrin clot architecture is increasingly associated with cardiovascular diseases; yet, little is known about how fibrin networks are affected by small molecules that alter fibrinogen structure. Based on previous evidence that S-nitrosoglutathione (GSNO) alters fibrinogen secondary structure and fibrin polymerization kinetics, we hypothesized that GSNO would alter fibrin microstructure. Accordingly, we treated human platelet-poor plasma with GSNO (0.01-3.75 mM) and imaged thrombin induced fibrin networks using multiphoton microscopy. Using custom designed computer software, we analyzed fibrin microstructure for changes in structural features including fiber density, diameter, branch point density, crossing fibers and void area. We report for the first time that GSNO dose-dependently decreased fibrin density until complete network inhibition was achieved. At low dose GSNO, fiber diameter increased 25%, maintaining clot void volume at approximately 70%. However, at high dose GSNO, abnormal irregularly shaped fibrin clusters with high fluorescence intensity cores were detected and clot void volume increased dramatically. Notwithstanding fibrin clusters, the clot remained stable, as fiber branching was insensitive to GSNO and there was no evidence of fiber motion within the network. Moreover, at the highest GSNO dose tested, we observed for the first time, that GSNO induced formation of fibrin agglomerates. Taken together, low dose GSNO modulated fibrin microstructure generating coarse fibrin networks with thicker fibers; however, higher doses of GSNO induced abnormal fibrin structures and fibrin agglomerates. Since GSNO maintained clot void volume, while altering fiber diameter it suggests that GSNO may modulate the remodeling or inhibition of fibrin networks over an optimal concentration range.


Regulation of arachidonic acid metabolism by macrophage activation.
Levels of zymosan-induced arachidonic acid (20:4) metabolism by peritoneal macrophages elicited with inflammatory agents and resident macrophages were similar. Thyioglycollate (THIO)-elicited macrophages represented the exception; however, the diminished metabolism by these cells was reproduced by exposing resident cells to 5 mg/ml THIO broth in vitro. In contrast, reduced prostaglandin synthesis by macrophages from mice variously treated with the immunologic agents, Corynebacterium parvum or Bacille Calmette Guérin (BCG), closely correlated with enhanced antitoxoplasma activity, one measure of macrophage activation. This relationship, although not causative, suggested that the capacity for 20:4 metabolism is a function of the macrophage activation state. Modulation of macrophage 20:4 metabolism in vivo apparently required factors in addition to lymphocyte-derived products. Treatment of resident macrophages in vitro with BCG lymphokine was without effect on 20:4 release or prostaglandin synthesis. Activated macrophages from animals inoculated i.p. with C. parvum exhibited reduced 20:4 release and also failed to metabolize 70% of the 20:4 released in response to a zymosan stimulus. Consequently, the quantities of 20:4 metabolites formed were significantly less than expected from 20:4 release. These activated macrophages displayed greatly reduced synthesis of prostacylcin and leukotriene C compared with other 20:4 metabolites. It appeared that factors that regulate macrophage 20:4 metabolism influence the level of the inducible phospholipase and synthetic enzymes for specific 20:4 oxygenated products.


Genotypic variation in drought stress response and subsequent recovery of wheat (Triticum aestivum L.).
Three wheat (Triticum aestivum L.) genotypes, Sadovo, Katya and Prelom, with different tolerance to drought were comparatively evaluated in terms of leaf respiratory responses to progressing dehydration and consecutive rewatering. Under drought stress, the respiration of all varieties gradually decreased, as the drought-tolerant Katya showed the most pronounced decline at earlier stages of dehydration. When water stress intensified, this genotype gave relatively stable respiration rates compared with the drought-sensitive varieties. Additionally, dehydrated Katya leaves displayed lower stomatal conductance and higher photosynthesis values, which resulted in greater water use efficiency during the dehydration period. Combination of drought stress and short-term changes in leaf temperature also induced genotype-specific response that differed from the response to drought only. Over the whole temperature range, the leaves of Katya exposed to dehydration for 14 days, showed higher respiration rates compared to the drought-sensitive varieties. The sensitive varieties maintained higher respiration rates under control conditions and mild dehydration, and very low rates under severe drought. In Katya, respiration and photosynthesis were fully restored from the stress within the first day of rewatering. The drought-sensitive genotypes displayed a considerably slower recovering capacity. The results are discussed in terms of possible physiological mechanisms underlying plant tolerance to drought.


Evolution of dietary preferences and the innate urge to heal: Drug discovery lessons from Ayurveda.
Highly specialized and functionally integrated cognitive systems facilitate hedonistic and healthy food preferences. Guided by survival needs, flavor preferences not only select safe, nutritious dietary components, but also those with negligible calorific value but significant health benefits, for example, spices. Feeding behavior, both innate and acquired, is guided not only by taste receptors on the tongue but also visceral organs. The gustatory cortex receives information from all senses, not just taste, suggesting multiple checkpoints in predicting and evaluating healthy foods. Ayurvedic interpretation of 'rasa' as chemistry is compatible with medicinal value of diets because, taste and odor are chemosensory perceptions. As flavor and taste are linked to the chemical structure of compounds, taste might offer clues about pharmacological activity. Ayurvedic idea of vipaka, or post digestive perception of taste, recognizes the extended role of taste receptors beyond the tongue and stretching into the viscera. Ayurvedic wisdom is consistent with evolutionary guideposts that suggest three successive stages of nutritional appraisal: before, during, and after ingesting food. While olfaction induces affinity or revulsion even before ingestion, gustatory receptors on the tongue evaluates nutritional value upon contact, and the chemoreceptors in the deeper metabolic systems probably pronounce the final verdict on the nutritive and health benefits of ingested substances. Alliesthesia, neophobia, and the extreme variation in human T2R genes (coding for bitterness receptors) illustrate the importance of adaptive learning of dietary preferences. These evolutionary clues are compatible with the Ayurvedic principle of 'rasa', in facilitating the process of drug discovery.


Assessing equine embryo developmental competency by time-lapse image analysis.
The timing of early mitotic events during preimplantation embryo development is important for subsequent embryogenesis in many mammalian species, including mouse and human, but, to date, no study has closely examined mitotic timing in equine embryos from oocytes obtained by ovum pick-up. Here, cumulus-oocyte complexes were collected by transvaginal follicular aspiration, matured invitro and fertilised via intracytoplasmic sperm injection. Each fertilised oocyte was cultured up to the blastocyst stage and monitored by time-lapse imaging for the measurement of cell cycle intervals and identification of morphological criteria indicative of developmental potential. Of the 56 fertilised oocytes, 35 initiated mitosis and 11 progressed to the blastocyst stage. Analysis of the first three mitotic divisions in embryos that formed blastocysts determined that typical blastocyst timing (median±IQR) is 30.0±17.5min, 8.8±1.7h and 0.6±1.4h respectively. Frequent cellular fragmentation, multipolar divisions and blastomere exclusion suggested that equine embryos likely contend with a high incidence of chromosomal missegregation. Indeed, chromosome-containing micronuclei and multinuclei with extensive DNA damage were observed throughout preimplantation embryogenesis. This indicates that time-lapse image analysis may be used as a non-invasive method to assess equine embryo quality in future studies.


Thermotolerance and heat acclimation may share a common mechanism in humans.
Thermotolerance and heat acclimation are key adaptation processes that have been hitherto viewed as separate phenomena. Here, we provide evidence that these processes may share a common basis, as both may potentially be governed by the heat shock response. We evaluated the effects of a heat shock response-inhibitor (quercetin; 2,000 mg/day) on established markers of thermotolerance [gastrointestinal barrier permeability, plasma TNF-α, IL-6, and IL-10 concentrations, and leukocyte heat shock protein 70 (HSP70) content]. Heat acclimation reduced body temperatures, heart rate, and physiological strain during exercise/heat stress) in male subjects (n = 8) completing a 7-day heat acclimation protocol. These same subjects completed an identical protocol under placebo supplementation (placebo). Gastrointestinal barrier permeability and TNF-α were increased on the 1st day of exercise/heat stress in quercetin; no differences in these variables were reported in placebo. Exercise HSP70 responses were increased, and plasma cytokines (IL-6, IL-10) were decreased on the 7th day of heat acclimation in placebo; with concomitant reductions in exercise body temperatures, heart rate, and physiological strain. In contrast, gastrointestinal barrier permeability remained elevated, HSP70 was not increased, and IL-6, IL-10, and exercise body temperatures were not reduced on the 7th day of heat acclimation in quercetin. While exercise heart rate and physiological strain were reduced in quercetin, this occurred later in exercise than with placebo. Consistent with the concept that thermotolerance and heat acclimation are related through the heat shock response, repeated exercise/heat stress increases cytoprotective HSP70 and reduces circulating cytokines, contributing to reductions in cellular and systemic markers of heat strain. Exercising under a heat shock response-inhibitor prevents both cellular and systemic heat adaptations.


Are female sex workers able to negotiate condom use with male clients? The case of mobile FSWs in four high HIV prevalence states of India.
Condom promotion among female sex workers (FSWs) is a key intervention in India's National AIDS Control Program. However, there is limited understanding of how FSWs negotiate condom use with male clients, particularly in the context of their mobility for sex work. The objective of this study is to examine the factors associated with the mobile FSWs' ability to refuse unsafe sex and successfully negotiate condom use with unwilling male clients. Data for 5498 mobile FSWs from a cross-sectional survey conducted in 22 districts of four states in southern India were analyzed. Questions assessed FSWs' ability to refuse clients unprotected sex, convince unwilling clients for condom use and negotiate condom use in a new location. Logistic regression models were constructed to examine the association between socio-demographics, economic vulnerability, sex work practice, and program exposure and condom negotiation ability. A majority of FSWs (60%) reported the ability to refuse clients for unprotected sex, but less than one-fifth reported the ability to successfully convince an unwilling client to use a condom or to negotiate condom use in a new site. Younger and older mobile FSWs compared to those who were in the middle age group, those with longer sex work experience, with an income source other than sex work, with program exposure and who purchased condoms for use, reported the ability to refuse unprotected sex, to successfully negotiate condom use with unwilling clients and to do so at new sites. FSWs need to be empowered to not only refuse unprotected sex but also to be able to motivate and convince unwilling clients for condom use, including those in new locations. In addition to focusing on condom promotion, interventions must address the factors that impact FSWs' ability to negotiate condom use.


Functional Transcriptomics in Diverse Intestinal Epithelial Cell Types Reveals Robust MicroRNA Sensitivity in Intestinal Stem Cells to Microbial Status.
Gut microbiota play an important role in regulating the development of the host immune system, metabolic rate, and at times, disease pathogenesis. The factors and mechanisms that mediate interactions between microbiota and the intestinal epithelium are not fully understood. We provide novel evidence that microbiota may control intestinal epithelial stem cell (IESC) proliferation in part through microRNAs (miRNAs). We demonstrate that miRNA profiles differ dramatically across functionally distinct cell types of the mouse jejunal intestinal epithelium and that miRNAs respond to microbiota in a highly cell type-specific manner. Importantly, we also show that miRNAs in IESCs are more prominently regulated by microbiota compared with miRNAs in any other intestinal epithelial cell subtype. We identify miR-375 as one miRNA that is significantly suppressed by the presence of microbiota in IESCs. Using a novel method to knockdown gene and miRNA expression ex vivo enteroids, we demonstrate that we can knock down gene expression in Lgr5+ IESCs. Furthermore, when we knock down miR-375 in IESCs, we observe significantly increased proliferative capacity. Understanding the mechanisms by which microbiota regulate miRNA expression in IESCs and other intestinal epithelial cell subtypes will elucidate a critical molecular network that controls intestinal homeostasis and, given the heightened interest in miRNA-based therapies, may offer novel therapeutic strategies in the treatment of gastrointestinal diseases associated with altered IESC function.


Effectiveness of nursing-led inpatient care for patients with post-acute health care needs: secondary data analysis from a programme of randomized controlled trials.
To determine whether transfer to a nursing-led inpatient unit (NLIU) prior to discharge from hospital can improve clinical outcome and reduce length of stay and readmission rate for medically stable post-acute patients assessed as requiring inpatient care. Retrospective secondary data analysis of individual patient data (n=471) from a programme of three, purposefully replicated, pragmatic randomized controlled trials. Patients were referred to the NLIU by their consultant (attending doctor/surgeon) for nursing-led subacute/post-acute care and randomly allocated to a treatment group for planned transfer to the NLIU for the remainder of their hospital stay or to a control group for traditional consultant-led care in acute wards. Outcome measures were physical function (Barthel Index), length of stay, discharge destination, mortality, psychological well-being (General Health Questionnaire-12), health-related distress (Nottingham Health Profile Distress Index), incidence of complications and readmission within 7, 28, 90 and 180 days. Patients allocated to the NLIU showed greater improvement in physical function (P<0.001) and were more likely to be discharged to live independently in the community than controls [odds ratio (OR)=0.42, P=0.001] although they spent longer in hospital (P= 0.003). They showed greater improvement in psychological well-being (P = 0.001) and health-related distress (P =0.025) and a lower incidence of pressure ulcers (OR=0.33, P=0.011). Transfer to a NLIU can have a beneficial effect on outcomes of care for post-acute patients with complex health and social needs although length of stay is longer. This study strengthens the evidence of effectiveness of the NLIU model of care and provides evidence of effectiveness of post-acute and subacute models of care.


Gene expression profile of osseointegration of a hydrophilic compared with a hydrophobic microrough implant surface.
To compare the gene expression profile of osseointegration associated with a moderately rough and a chemically modified hydrophilic moderately rough surface in a human model. Eighteen solid screw-type cylindrical titanium implants, 4 mm long and 2.8 mm wide, with either a moderately rough (SLA) or a chemically modified moderately rough (SLActive) surface were surgically inserted in the retromolar area of nine human volunteers. The devices were removed using a trephine following 4, 7 and 14 days of healing. The tissue surrounding the implant was harvested, total RNA was extracted and microarray analysis was carried out to identify the differences in the transcriptome between the SLA and SLActive surfaces at days 4, 7 and 14. There were no functionally relevant gene ontology categories that were over-represented in the list of genes that were differentially expressed at day 4. However, by day 7, osteogenesis- and angiogenesis-associated gene expression were up-regulated on the SLActive surface. Osteogenesis and angiogenesis appeared to be regulated by BMP and VEGF signalling, respectively. By day 14, VEGF signalling remains up-regulated on the SLActive surface, while BMP signalling was up-regulated on the SLA surface in what appeared to be a delayed compensatory response. Furthermore, neurogenesis was a prominent biological process within the list of differentially expressed genes, and it was influenced by both surfaces. Compared with SLA, SLActive exerts a pro-osteogenic and pro-angiogenic influence on gene expression at day 7 following implant insertion, which may be responsible for the superior osseointegrative properties of this surface.


Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial.
To evaluate the effect of three intravitreal injections of bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular edema (DME). In this prospective, placebo-controlled, randomized clinical trial, 115 eyes of 101 patients with refractory DME were included. Subjects were randomly assigned to one of the three study arms: 1) three injections of IVB (1.25 mg/0.05 ml) at 6-week intervals, 2) combined IVB and IVT (1.25 mg/0.05 ml and 2 mg/0.05 ml respectively) followed by two injections of IVB at 6-week intervals, and 3) sham injection (control group). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA ) and incidence of potential adverse events. Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was -95.7 microm (95% CI, -172.2 to -19.26) in the IVB group, -92.1 microm (95% CI, -154.4 to -29.7) in the IVB/IVT group, and 34.9 microm (95% CI, 7.9 to 61.9) in the control group. There was a significant difference between the IVB and control groups (P = 0.012) and between the IVB/IVT and control groups (P = 0.022). Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. In terms of BCVA change compared to the baseline at 24 weeks, the differences between the IVB and control groups (P = 0.01) and also between the IVB/IVT and control groups (P = 0.006) were significant. No significant differences were detected in the changes of CMT and BCVA between the IVB and IVB/IVT groups (P = 0.99). Anterior chamber reaction was noticed in eight (19.5%) and seven (18.9%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of IOP occurred in three eyes (8.1%) in the IVB/IVT group. Three consecutive intravitreal injections of bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the first injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up.


The polyp prevention trial II: dietary intervention program and participant baseline dietary characteristics.
The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial to evaluate whether a low-fat, high-dietary fiber, high-fruit and -vegetable eating pattern will reduce the recurrence of adenomatous polyps of the large bowel. Men and women who had one or more adenomas removed recently were randomized into either the intervention (n = 1037) or control (n = 1042) arms. Food frequency questionnaire data indicate that PPT participants at the beginning of the trial consumed 36.8% of total energy from fat, 9.7 g of dietary fiber/1000 kcal, and 3.8 daily servings of fruits and vegetables. Baseline dietary characteristics, including intake of fat, fiber, and fruits and vegetables, as well as other macro- and micronutrients, were similar in the two study groups. The intervention participants receive extensive dietary and behavioral counseling to achieve the PPT dietary goals of 20% of total energy from fat, 18 g/1000 kcal of dietary fiber, and 5-8 daily servings (depending on total caloric intake) of fruits and vegetables. Control participants do not receive such counseling and are expected to continue their usual intake. Dietary intake in both groups is mentioned annually using a 4-day food record (also completed at 6 months by intervention participants only) and a food frequency questionnaire, with a 10% random sample of participants completing an annual unscheduled 24-h telephone recall. Blood specimens are drawn and analyzed annually for lipids and carotenoids. This article provides details on the rationale and design of the PPT dietary intervention program and describes the participant baseline dietary intake data characteristics.


An intracellular replication niche for Vibrio cholerae in the amoeba Acanthamoeba castellanii.
Vibrio cholerae is a human pathogen and the causative agent of cholera. The persistence of this bacterium in aquatic environments is a key epidemiological concern, as cholera is transmitted through contaminated water. Predatory protists, such as amoebae, are major regulators of bacterial populations in such environments. Therefore, we investigated the interaction between V. cholerae and the amoeba Acanthamoeba castellanii at the single-cell level. We observed that V. cholerae can resist intracellular killing. The non-digested bacteria were either released or, alternatively, established a replication niche within the contractile vacuole of A. castellanii. V. cholerae was maintained within this compartment even upon encystment. The pathogen ultimately returned to its aquatic habitat through lysis of A. castellanii, a process that was dependent on the production of extracellular polysaccharide by the pathogen. This study reinforces the concept that V. cholerae is a facultative intracellular bacterium and describes a new host-pathogen interaction.


Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms.
Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms in Drosophila clock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate that Drosophila clock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes, period and timeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci and per gene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.


Measures of abstinence in clinical trials: issues and recommendations.
A workgroup formed by the Society for Research on Nicotine and Tobacco reviewed the literature on abstinence measures used in trials of smoking cessation interventions. We recommend that trials report multiple measures of abstinence. However, at a minimum we recommend that trial: (a) report prolonged abstinence (i.e., sustained abstinence after an initial period in which smoking is not counted as a failure) as the preferred measure, plus point prevalence as a secondary measure; (b) use 7 consecutive days of smoking or smoking on > or = 1 day of 2 consecutive weeks to define treatment failure; (c) include non-cigarette tobacco use, but not nicotine medications in definitions of failure; and (d) report results from survival analysis to describe outcomes more fully. Trials of smokers willing to set a quit date should tie all follow-ups to the quit date and report 6- and/or 12-month abstinence rates. For these trials, we recommend an initial 2-week grace period for prolonged abstinence definitions; however, the period may vary, depending on the presumed mechanism of the treatment. Trials of smokers who may not be currently trying to quit should tie follow-up to the initiation of the intervention and should report a prolonged abstinence measure of > or = 6-month duration and point prevalence rates at 6- and 12-month follow-ups. The grace period for these trials will depend on the time necessary for treatment dissemination, which will vary depending on the treatment, setting, and population. Trials that use short-term follow-ups (< or = 3 months) to demonstrate possible efficacy should report a prolonged abstinence measure of > or = 4 weeks. We again recommend a 2-week grace period; however, that period can vary.


Intranasal Steroid Use for Otitis Media with Effusion: Ongoing Opportunities for Quality Improvement.
Objectives Our objectives were (1) to assess patterns of intranasal steroid administration when otitis media with effusion (OME) has been diagnosed in children, (2) to investigate whether usage varies according to visit setting, and (3) to determine if practice gaps are such that quality improvement could be tracked. Study Design Cross-sectional analysis of an administrative database. Subjects and Methods National Ambulatory and Hospital Ambulatory Medical Care Surveys, 2005 to 2012; univariate, multivariate, and stratified analyses of intranasal steroid usage were performed. The primary outcome was intranasal steroid administration, and the primary predictor was a diagnosis of OME. The impact of location of service was also analyzed. Results Data representing 1,943,177,903 visits demonstrated that intranasal steroids were administered in 10.0% of visits in which OME was diagnosed, in comparison to 3.5% of visits in which OME was not diagnosed (univariate odds ratio, 3.07; 95% confidence interval [CI], 1.85-5.08; P < .001). After adjusting for age, sex, race/ethnicity, and other confounding conditions, multivariate analysis demonstrated that OME remained associated with an increase in intranasal steroid usage (odds ratio, 3.58; 95% CI, 1.60-8.01; P = .002). This practice pattern was more prevalent in the ambulatory office setting (risk difference 6.6%, P < .001) and less seen in a hospital-based office or emergency department. Conclusion Despite randomized controlled trials showing a lack of efficacy for isolated OME, nasal steroids continue to be used in treating children with OME in the United States. Related quality improvement opportunities to prevent usage of an ineffective treatment exist.


Cohort Randomised Controlled Trial of a Multifaceted Podiatry Intervention for the Prevention of Falls in Older People (The REFORM Trial).
Falls are a major cause of morbidity among older people. A multifaceted podiatry intervention may reduce the risk of falling. This study evaluated such an intervention. Pragmatic cohort randomised controlled trial in England and Ireland. 1010 participants were randomised (493 to the Intervention group and 517 to Usual Care) to either: a podiatry intervention, including foot and ankle exercises, foot orthoses and, if required, new footwear, and a falls prevention leaflet or usual podiatry treatment plus a falls prevention leaflet. The primary outcome was the incidence rate of self-reported falls per participant in the 12 months following randomisation. Secondary outcomes included: proportion of fallers and those reporting multiple falls, time to first fall, fear of falling, Frenchay Activities Index, Geriatric Depression Scale, foot pain, health related quality of life, and cost-effectiveness. In the primary analysis were 484 (98.2%) intervention and 507 (98.1%) control participants. There was a small, non statistically significant reduction in the incidence rate of falls in the intervention group (adjusted incidence rate ratio 0.88, 95% CI 0.73 to 1.05, p = 0.16). The proportion of participants experiencing a fall was lower (49.7 vs 54.9%, adjusted odds ratio 0.78, 95% CI 0.60 to 1.00, p = 0.05) as was the proportion experiencing two or more falls (27.6% vs 34.6%, adjusted odds ratio 0.69, 95% CI 0.52 to 0.90, p = 0.01). There was an increase (p = 0.02) in foot pain for the intervention group. There were no statistically significant differences in other outcomes. The intervention was more costly but marginally more beneficial in terms of health-related quality of life (mean quality adjusted life year (QALY) difference 0.0129, 95% CI -0.0050 to 0.0314) and had a 65% probability of being cost-effective at a threshold of £30,000 per QALY gained. There was a small reduction in falls. The intervention may be cost-effective. ISRCTN ISRCTN68240461.


The Agrobacterium tumefaciens virB7 gene product, a proposed component of the T-complex transport apparatus, is a membrane-associated lipoprotein exposed at the periplasmic surface.
The Agrobacterium tumefaciens virB7 gene product contains a typical signal sequence ending with a consensus signal peptidase II cleavage site characteristic of bacterial lipoproteins. VirB7 was shown to be processed as a lipoprotein by (i) in vivo labeling of native VirB7 and a VirB7::PhoA fusion with [3H]palmitic acid and (ii) inhibition of VirB7 processing by globomycin, a known inhibitor of signal peptidase II. A VirB7 derivative sustaining a Ser substitution for the invariant Cys-15 residue within the signal peptidase II cleavage site could not be visualized immunologically and failed to complement a delta virB7 mutation, establishing the importance of this putative lipid attachment site for VirB7 maturation and function. VirB7 partitioned predominantly with outer membrane fractions from wild-type A348 cells as well as a delta virB operon derivative transformed with a virB7 expression plasmid. Expression of virB7 fused to phoA, the alkaline phosphatase gene of Escherichia coli, gave rise to high alkaline phosphatase activities in E. coli and A. tumefaciens cells, providing genetic evidence for the export of VirB7 in these hosts. VirB7 was shown to be intrinsically resistant to proteinase K; by contrast, a VirB7::PhoA derivative was degraded by proteinase K treatment of A. tumefaciens spheroplasts and remained intact upon treatment of whole cells. Together, the results of these studies favor a model in which VirB7 is topologically configured as a monotopic protein with its amino terminus anchored predominantly to the outer membrane and with its hydrophilic carboxyl domain located in the periplasmic space. Parallel studies of VirB5, VirB8, VirB9, and VirB10 established that each of these membrane-associated proteins also contains a large periplasmic domain whereas VirB11 resides predominantly or exclusively within the interior of the cell.


Alcohol-Induced C-N Bond Cleavage of Cyclometalated N-Heterocyclic Carbene Ligands with a Methylene-Linked Pendant Imidazolium Ring.
Reaction of the pentamethylcyclopentadienyl rhodium iodide dimer [Cp*RhI2 ]2 with 1,1'-diphenyl-3,3'-methylenediimidazolium diiodide in non-alcohol solvents, in the presence of base, led to the formation of bis-carbene complex [Cp*Rh(bis-NHC)I]I (bis-NHC=1,1'-diphenyl-4,4'-methylenediimidazoline-5,5'-diylidene). In contrast, when employing alcohols as the solvent in the same reaction, cleavage of a methylene C-N bond is observed, affording ether-functionalized (cyclometalated) carbene ligands coordinated to the metal center and the concomitant formation of complexes with a coordinated imidazole ligand. Studies employing other 1,1'-diimidazolium salts indicate that the cyclometalation step is a prerequisite for the activation/scission of the C-N bond and, based on additional experimental data, a SN 2 mechanism for the reaction is tentatively proposed.


Use of flecainide for refractory atrial tachycardia of pregnancy.
Sustained arrhythmias during pregnancy are uncommon. However, when they do occur, atrial tachycardias are usually amenable to pharmacological or electrical therapy. We describe a case of sustained atrial tachycardia in a pregnant patient. The tachycardia was resistant to commonly used antiarrhythmic drugs and to cardioversion but rapidly responded to flecainide, with return to sinus rhythm until the patient was delivered of a healthy baby.


Direct demonstration of macula densa-mediated renin secretion.
An in vitro method has been used to examine whether secretion of renin from the juxtaglomerular apparatus is affected by changes in the sodium chloride concentration of the tubular fluid at the macula densa. Single juxtaglomerular apparatuses were microdissected from rabbits and the tubule segment containing the macula densa was perfused, while simultaneously the entire juxtaglomerular apparatus was superfused, and the fluid was collected for renin measurement. In this preparation, in which influences from renal nerves and local hemodynamic effects are eliminated, a decrease in the tubular sodium chloride concentration at the macula densa results in a prompt stimulation of the renin release rate.


Low Back Pain With Impact at 17 Years of Age Is Predicted by Early Adolescent Risk Factors From Multiple Domains: Analysis of the Western Australian Pregnancy Cohort (Raine) Study.
Study Design Prospective cohort study of the Western Australian Pregnancy Cohort (Raine) Study. Background Low back pain (LBP) commonly develops in adolescence and is a significant risk factor for adult LBP. A broad range of factors have been associated with the development of adolescent LBP, but prior literature has limitations related to characterization of LBP and the scope of risk factors considered. Objective This study aimed to identify potential factors contributing to the development of LBP, with and without impact, at 17 years of age, utilizing a broad range of exposures at 14 years of age. Methods Data from 1088 participants (52.1% female) with "no LBP," "LBP with minimal impact," and "LBP with impact" at 17 years of age and a range of measures from multiple domains, including spinal pain, physical, psychological, social, and lifestyle, at 14 years of age were collected for the study. Multivariable multinomial logistic regression was used to estimate the association of potential mechanistic factors at 14 years of age with LBP at 17 years of age. Results Female sex and back pain at 14 years of age were strongly associated with LBP at 17 years of age. Potential mechanistic factors for LBP outcomes at 17 years of age included exposures from the pain (neck/shoulder pain) and physical domains (standing posture subgroup membership, back muscle endurance, throwing distance), psychological domain (somatic complaints, aggressive behavior), social domain (socioeconomic area), and lifestyle domain (exercise out of school). Conclusion The findings support the multidimensional nature of adolescent LBP and highlight the challenge this presents for epidemiological research, clinical practice, and prevention initiatives in the general population. Level of Evidence Prognosis, level 1b. J Orthop Sports Phys Ther 2017;47(10):752-762. doi:10.2519/jospt.2017.7464.


Progress toward a group B streptococcal vaccine.
Streptococcus agalactiae (group B Streptococcus, GBS) is a leading cause of severe invasive disease in neonate, elderly, and immunocompromised patients worldwide. Despite recent advances in the diagnosis and intrapartum antibiotic prophylaxis (IAP) of GBS infections, it remains one of the most common causes of neonatal morbidity and mortality, causing serious infections. Furthermore, recent studies reported an increasing number of GBS infections in pregnant women and elderly. Although IAP is effective, it has several limitations, including increasing antimicrobial resistance and late GBS infection after negative antenatal screening. Maternal immunization is the most promising and effective countermeasure against GBS infection in neonates. However, no vaccine is available to date, but two types of vaccines, protein subunit and capsular polysaccharide conjugate vaccines, were investigated in clinical trials. Here, we provide an overview of the GBS vaccine development status and recent advances in the development of immunoassays to evaluate the GBS vaccine clinical efficacy.


Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder.
Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.


Comparison of 1-week and 2-week recall periods for caregiver-reported diarrhoeal illness in children, using nationally representative household surveys.
Diarrhoeal outcomes in children are often ascertained using caregiver-reported symptoms, which are subject to a variety of biases and methodological challenges. One source of bias is the time window used for reporting diarrhoeal illness and the ability of caregivers to accurately recall episodes in children. Diarrhoea period prevalence in children under five was determined using two similarly administered, nationally representative household surveys: Performance Monitoring and Accountability 2020 (PMA2020) (1-week recall, N = 14 603) and Demographic and Health Surveys (DHS) (2-week recall, N = 66 717). Countries included in the analysis were the Democratic Republic of the Congo, Ethiopia, Ghana, Kenya and Uganda. Diarrhoea period prevalence estimates were compared and water, sanitation and hygiene risk factors were analysed. Childhood diarrhoea prevalence using 1-week recall (PMA2020) pooled across countries was 21.4% [95% confidence interval (CI): 19.9%, 22.9%] versus 16.0% using 2-week recall (DHS) (95% CI: 15.4%, 16.5%). In stratified analyses for all five countries, the number of diarrhoea cases detected was consistently higher using 1-week recall versus 2-week recall. The key risk factors identified in the PMA2020 data that were not associated with diarrhoeal episodes or were attenuated in the DHS data included: the main sanitation classifications for households, disposal method used for child faeces, number of household members and wealth quintiles. For nationally representative household surveys assessing childhood diarrhoea period prevalence, a 2-week recall period may underestimate diarrhoea prevalence compared with a 1-week period. The household sanitation facility and practices remain key risk factors for diarrhoeal disease in children under five.


[The Isenheim altarpiece: religion, art and medicine].
Northern Europe at the beginning of the 16th Century was in turmoil as a result of religious and political dissention, epidemics of plague, syphilis, ergotism, and famine, and the threat of the Ottoman Empire. In Alsace, a fulcrum between Germany, France, Switzerland and the Netherlands, Grünewald painted his celebrated and complex altarpiece at Isenheim in a convent chapel of the Antonine religious order that kept a hospital for the care of patients suffering from ergotism, plague, syphilis and other illnesses. The ten paintings of this altarpiece convey a series of religious, medical and political meanings, with the scenes of the Crucifixion and the Resurrection being thought to play an integral part of the curative process. This was because patients could be soothed by comparing their suffering to that of Christ on the cross and could console themselves by the Resurrection. The portrait of Christ in the cross is astounding in its realism and naturalism. It represents, with great pathological veracity, a tortured body in agony, a break with previous traditional representations of this event. Impressive pathological detail is also given to a figure in the Temptation scene. The entire work is suffused with religious connotations provided by the composition, the forms and the richness and sophisticated use of colors. Although Grünewald's paintings are few and the facts of his personal life sparse, it is known he married a Jewish woman, supported the peasant revolts, and was probably a Lutheran in a Catholic area. While Grünewald is considered the epitome of a German artist, the universal projections of his art have influenced physicians and the artistic productions of many painters, writers, musicians and sculptors throughout the world.


Long-term complications and risk of other serious infections following invasive Haemophilus influenzae serotype b disease in vaccinated children.
This study describes the long-term complications in children with Haemophilus influenzae serotype b (Hib) vaccine failure and to determine their risk of other serious infections. The families of 323 children with invasive Hib disease after appropriate vaccination (i.e. vaccine failure) were contacted to complete a questionnaire relating to their health and 260 (80.5%) completed the questionnaire. Of the 124 children with meningitis, 18.5% reported serious long-term sequelae and a further 12.1% of parents attributed other problems to Hib meningitis. Overall, 14% (32/231 cases) of otherwise healthy children and 59% (17/29 cases) of children with an underlying condition developed at least one other serious infection requiring hospital admission. In a Poisson regression model, the risk of another serious infection was independently associated with the presence of an underlying medical condition (incidence risk ratio (IRR) 7.6, 95% CI 4.8-12.1; p<0.0001), both parents having had a serious infection (IRR 4.1, 95% CI 1.6-10.3; p=0.003), requirement of more than two antibiotic courses per year (IRR 2.3, 95% CI 1.4-3.6; p=0.001) and the presence of a long-term complication after Hib infection (IRR 1.8, 95% CI 1.1-3.1; p=0.03). Thus, rates of long-term sequelae in children with vaccine failure who developed Hib meningitis are similar to those in unvaccinated children in the pre-vaccine era. One in seven otherwise healthy children (14%) with Hib vaccine failure will go on to suffer another serious infection requiring hospital admission in childhood, which is higher than would be expected for the UK paediatric population.


Initial postmarketing experience with crotalidae polyvalent immune Fab for treatment of rattlesnake envenomation.
We describe our postmarketing experience with patients receiving Crotalidae polyvalent immune Fab (CroFab; FabAV) antivenom for treatment of rattlesnake envenomation. The charts of 28 patients admitted between March 1 and September 9, 2001, with rattlesnake envenomation and treated with FabAV were reviewed for demographic information, time until antivenom treatment, laboratory findings, evidence of hypersensitivity reaction, length of hospital stay, and readmission to the hospital. All patients had swelling, 20 patients had elevated prothrombin times (>14 seconds), 12 patients had low fibrinogen levels (<170 mg/dL), and 6 patients had thrombocytopenia (platelet count <120,000/mm(3)) on presentation. The total dose of FabAV ranged from 10 to 47 vials per patient. Hypofibrinogenemia was resistant to FabAV in some patients. On follow-up, recurrence of coagulopathy was detected in 3 patients, and recurrence of thrombocytopenia was detected in 1 patient. Two patients demonstrated delayed-onset severe thrombocytopenia. Recurrence or delayed-onset toxicity might have been underestimated because of incomplete follow-up in some patients. No acute hypersensitivity reactions occurred. Two patients reported mild symptoms of possible serum sickness on follow-up. FabAV effectively controlled the effects of envenomation; however, initial control of coagulopathy was difficult to achieve in some cases, and recurrence or delayed-onset hematotoxicity was common. When initially managing hematotoxicity, a trend toward normalization of laboratory values might be a more reasonable end point for FabAV treatment than attainment of normal reference values in nonbleeding patients.


Ambulatory health services utilization in patients with dementia - Is there an urban-rural difference?
Due to demographic changes and an un-equal distribution of physicians, regional analyses of service utilization of elderly patients are crucial, especially for diseases with an impact like dementia. This paper focuses on dementia patients. The aim of the study is to identify differences in service utilization of incident dementia patients in urban and rural areas. Basis for the analysis were all insured persons of a German Health Insurance fund (the GEK) aged 65 years and older living in rural and urban areas. We focussed on physician contacts in the outpatient sector during the first year after an incidence diagnosis of dementia. Special attention was given to contacts with primary care physicians and neurologists/psychiatrists. The dementia cohort was analyzed together with a non-dementia control group drawn according to age, gender and amount of physician contacts. Uni- and bivariate as well as multivariate analysis were performed to estimate the influences on service utilization. Results show that the provision of primary care seems to be equally given in urban and rural areas. For specialists contacts however, rural patients are less likely to consult neurologists or psychiatrists. This trend can already be seen before the incident diagnosis of dementia. All consultations rise in the quarter of the incident dementia diagnosis compared to the control group. The results were also tested in a linear and a logistic regression, showing a higher chance for persons living in urban areas to visit a specialist and an overall higher rate in service utilization for dementia patients. Because of a probable increase in the number of dementia patients, service provision has to be accessible even in rural areas. Due to this and the fact that demographic change is happening at different paces in different regions, regional variations have to be considered to ensure the future service provision.


Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway.
Proteolytic processing of the amyloid precursor protein (APP) occurs via two alternative pathways, localized to different subcellular compartments, which result in functionally distinct outcomes. Cleavage by a beta-gamma sequence generates the Abeta peptide that plays a central role in Alzheimer's disease. In the case of alpha-gamma cleavage, a secreted neurotrophic molecule is generated and the Abeta peptide cleaved and destroyed. In both cases, a cytosolic APP intracellular domain (AICD) is generated. We have previously shown that coexpression of APP with the APP-binding protein Fe65 and the histone acetyltransferase Tip60 results in the formation of nuclear complexes (termed AFT complexes), which localize to transcription sites. We now show that blocking endocytosis or the pharmacological or genetic inhibition of the endosomal beta-cleavage pathway reduces translocation of AICD to these nuclear AFT complexes. AICD signaling further depends on active transport along microtubules and can be modulated by interference with both anterograde and retrograde transport systems. Nuclear signaling by endogenous AICD in primary neurons could similarly be blocked by inhibiting beta-cleavage but not by alpha-cleavage inhibition. This suggests that amyloidogenic cleavage, despite representing the minor cleavage pathway of APP, is predominantly responsible for AICD-mediated nuclear signaling.


Comparison of exposure to selected cigarette smoke constituents in adult smokers and nonsmokers in a European, multicenter, observational study.
This multicenter, observational study was conducted in three European countries (Germany, Switzerland, and the United Kingdom) to determine the exposure of adult cigarette smokers and nonsmokers to selected cigarette smoke constituents: 1,3-butadiene, 2-naphthylamine, 4-aminobiphenyl, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acrolein, benzene, carbon monoxide, nicotine, pyrene, and o-toluidine. Smokers were grouped by tar category (TC) according to the tar yield of their regular cigarette brand: TC1: ≤4 mg tar, TC2: 5-7 mg tar, and TC3: ≥8 mg tar [to the legal tar yield ceiling in the respective countries (10 or 12 mg tar)]. Levels of biomarkers of exposure to the aforementioned cigarette smoke constituents were compared between smokers and nonsmokers, and within smokers across tar categories. The full population consisted of 1,631 subjects (1,223 smokers and 408 nonsmokers). Biomarkers of exposure were analyzed for 1,558 subjects (valid case population) as follows: 1,159 smokers (TC1: n = 402, TC2: n = 379, TC3: n = 378), and 399 nonsmokers. Exposure levels were higher in smokers than nonsmokers and increased with increasing tar yield and cigarette consumption. An association of tar category and exposure level was observed for all smoke constituents, except pyrene, 4-aminobiphenyl, and o-toluidine, whereas only NNK exposure was different in all three tar categories. Smoking status and, among smokers, daily cigarette consumption and tar yield were observed to affect biomarker of exposure levels. This research provides a comprehensive evaluation of smoke constituent exposure of adult cigarette smokers and nonsmokers in three European countries.


Development and Evaluation of e-CA, an Electronic Mobile-Based Food Record.
Measures that capture diet as validly and reliably as possible are cornerstones of nutritional research, and mobile-based devices offer new opportunities to improve and simplify data collection. The balance between precision and acceptability of these data collection tools remains debated, and rigorous validations are warranted. Our objective was to develop and evaluate an electronic mobile-based food record for a research setting. We developed e-CA, which includes almost 900 foods and beverages classified in 14 categories and 60 subcategories. e-CA was evaluated using three different methods: (1) usability and acceptability through a logbook and qualitative interviews; (2) dietary intake accuracy through comparison with 2 unannounced 24-h phone recalls on overlapping days; and (3) reliability and process comparison with a paper-based food record in a laboratory setting with a randomized design. e-CA proved to be intuitive and practical and was perceived as modern, trendy, and fun. Comparisons of e-CA with 24-h telephone recalls or paper-based food records in a laboratory setting with two small convenient samples showed good agreement but highlighted the well-known difficulty of estimating portion sizes and a necessary learning time to use the app. e-CA is a functional tool that has the potential to facilitate food intake measurement for research by increasing the pleasure of using the food record tool and reducing the perceived burden for the participants. It also decreases the workload, costs and the risk of transcription errors for researchers.


Allergenic properties of enzymatically hydrolyzed peanut flour extracts.
Peanut flour is a high-protein, low-oil, powdered material prepared from roasted peanut seed. In addition to being a well-established food ingredient, peanut flour is also the active ingredient in peanut oral immunotherapy trials. Enzymatic hydrolysis was evaluated as a processing strategy to generate hydrolysates from peanut flour with reduced allergenicity. Soluble fractions of 10% (w/v) light roasted peanut flour dispersions were hydrolyzed with the following proteases: Alcalase (pH 8.0, 60°C), pepsin (pH 2.0, 37°C) or Flavourzyme (pH 7.0, 50°C) for 60 min. Western blotting, inhibition ELISA and basophil activation tests were used to examine IgE reactivity. Western blotting experiments revealed the hydrolysates retained IgE binding reactivity and these IgE-reactive peptides were primarily Ara h 2 fragments regardless of the protease tested. Inhibition ELISA assays demonstrated that each of the hydrolysates had decreased capacity to bind peanut-specific IgE compared with nonhydrolyzed controls. Basophil activation tests revealed that all hydrolysates were comparable (p > 0.05) to nonhydrolyzed controls in IgE cross-linking capacity. These results indicate that hydrolysis of peanut flour reduced IgE binding capacity; however, IgE cross-linking capacity during hydrolysis was retained, thus suggesting such hydrolysates are not hypoallergenic.


Battle of the eternal rivals: restoring functional p53 and inhibiting Polo-like kinase 1 as cancer therapy.
Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer.