Herpes simplex virus based gene therapy enhances the efficacy of mitomycin C for the treatment of human bladder transitional cell carcinoma.
Oncolytic replication competent herpes simplex virus type-1 (HSV) mutants have the ability to replicate in and kill malignant cells. We have previously reported the ability of replication competent HSV to control bladder cancer growth in an orthotopic murine model. We hypothesized that the combination of a chemotherapeutic agent used for intravesical treatment, namely mitomycin C (MMC) (Bristol-Myers Squibb Oncology, Princeton, New Jersey), and oncolytic HSV would exert a synergistic effect for the treatment of human transitional cell carcinoma. We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICP0 and ICP4, and selectively infects cancer cells, to treat the transitional cell carcinoma lines KU19-19 and SKUB. Cell survival was determined by lactate dehydrogenase assay for each agent as well as for drug-viral combinations from days 1 to 5. The isobologram method and the combination index method of Chou-Talalay were used to assess the synergistic effect. NV1066 enhanced MMC mediated cytotoxicity at all combinations tested for KU19-19 and SKUB. The combination of the 2 agents demonstrated a synergistic effect and allowed dose reduction by 12 and 10.4 times (NV1066), and by 3 and 156 times (MMC) for the treatment of KU19-19 and SKUB, respectively, while achieving an estimated 90% cell kill. These data provide the cellular basis for the clinical investigation of combined MMC and oncolytic HSV therapy for the treatment of bladder cancer.


Characterisation of drug resistance gene cassettes associated with class 1 integrons in clinical isolates of Escherichia coli from Taiwan, ROC.
The presence of class 1 integrons in clinical isolates of Escherichia coli was detected by PCR. Of 104 E. coli isolates from Kaohsiung, 54 (52%) carried class 1 integrons, with inserted DNA regions of 1-3 kb. These integrons were located on plasmids, as demonstrated by Southern hybridisation. DNA sequencing was used to identify the genetic content of the integron-variable regions. Different class 1 integrons contained various numbers, kinds and combinations of gene cassettes within their variable regions. These gene cassettes included those encoding resistance to trimethoprim (dfrIa, dfrV, dfr12 and dfr17), aminoglycosides (aadA1a, aadA2, aadA4 and aadB), chloramphenicol (cmlA), erythromycin (ereA2) and beta-lactams (blaP1). An integron carrying three inserted cassettes - dfr12-orJF-aadA2 - was present in 33 (61%) of the 54 isolates with class 1 integrons. Gene cassettes encoding resistance were expressed phenotypically. The results indicate that class 1 integrons are widespread in clinical E. coli isolates in Taiwan. The types, combinations and frequency of the gene cassettes in integrons may reflect the specific selective pressures to which the isolates were exposed and could provide useful surveillance data for relation to antibiotic usage information.


The evolution of vertebrate somatostatin receptors and their gene regions involves extensive chromosomal rearrangements.
Somatostatin and its related neuroendocrine peptides have a wide variety of physiological functions that are mediated by five somatostatin receptors with gene names SSTR1-5 in mammals. To resolve their evolution in vertebrates we have investigated the SSTR genes and a large number of adjacent gene families by phylogeny and conserved synteny analyses in a broad range of vertebrate species. We find that the SSTRs form two families that belong to distinct paralogons. We observe not only chromosomal similarities reflecting the paralogy relationships between the SSTR-bearing chromosome regions, but also extensive rearrangements between these regions in teleost fish genomes, including fusions and translocations followed by reshuffling through intrachromosomal rearrangements. These events obscure the paralogy relationships but are still tractable thanks to the many genomes now available. We have identified a previously unrecognized SSTR subtype, SSTR6, previously misidentified as either SSTR1 or SSTR4. Two ancestral SSTR-bearing chromosome regions were duplicated in the two basal vertebrate tetraploidizations (2R). One of these ancestral SSTR genes generated SSTR2, -3 and -5, the other gave rise to SSTR1, -4 and -6. Subsequently SSTR6 was lost in tetrapods and SSTR4 in teleosts. Our study shows that extensive chromosomal rearrangements have taken place between related chromosome regions in teleosts, but that these events can be resolved by investigating several distantly related species.


Maternal exposure to ambient air pollution and risk of early childhood cancers: A population-based study in Ontario, Canada.
There are increasing concerns regarding the role of exposure to ambient air pollution during pregnancy in the development of early childhood cancers. This population based study examined whether prenatal and early life (<1year of age) exposures to ambient air pollutants, including nitrogen dioxide (NO2) and particulate matter with aerodynamic diameters ≤2.5μm (PM2.5), were associated with selected common early childhood cancers in Canada. 2,350,898 singleton live births occurring between 1988 and 2012 were identified in the province of Ontario, Canada. We assigned temporally varying satellite-derived estimates of PM2.5 and land-use regression model estimates of NO2 to maternal residences during pregnancy. Incident cases of 13 subtypes of pediatric cancers among children up to age 6 until 2013 were ascertained through administrative health data linkages. Associations of trimester-specific, overall pregnancy and first year of life exposures were evaluated using Cox proportional hazards models, adjusting for potential confounders. A total of 2044 childhood cancers were identified. Exposure to PM2.5, per interquartile range increase, over the entire pregnancy, and during the first trimester was associated with an increased risk of astrocytoma (hazard ratio (HR) per 3.9μg/m3=1.38 (95% CI: 1.01, 1.88) and, HR per 4.0μg/m3=1.40 (95% CI: 1.05-1.86), respectively). We also found a positive association between first trimester NO2 and acute lymphoblastic leukemia (ALL) (HR=1.20 (95% CI: 1.02-1.41) per IQR (13.3ppb)). In this population-based study in the largest province of Canada, results suggest an association between exposure to ambient air pollution during pregnancy, especially in the first trimester and an increased risk of astrocytoma and ALL. Further studies are required to replicate the findings of this study with adjustment for important individual-level confounders.


hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large-conductance calcium-activated potassium channel beta subunit family.
We cloned two beta subunits of large-conductance calcium-activated potassium (BK) channels, hKCNMB3 (BKbeta1) and hKCNMB4 (BKbeta4). Profiling mRNA expression showed that hKCNMB3 expression is enriched in testis and hKCNMB4 expression is very prominent in brain. We coexpressed BK channel alpha (BKalpha) and BKbeta4 subunits in vitro in CHO cells. We compared BKalpha/beta4 mediated currents with those of smooth muscle BKalpha/beta1 channels. BKbeta4 slowed activation kinetics more significantly, led to a steeper apparent calcium sensitivity, and shifted the voltage range of BK current activation to more negative potentials than BKbeta1. BKalpha/beta4 channels were not blocked by 100 nM charybdotoxin or iberiotoxin, and were activated by 17beta-estradiol.


Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.
High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset. In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model. We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period. High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. National Health and Medical Research Council Australia and MS Society UK.


Higher-level motion detection deficit in Parkinson's disease.
Previous research has suggested that Parkinson's disease (PD) impairs motion perception. First-order motion consists of moving luminance-defined attributes. Second-order motion, on the other hand, consists of moving patterns whose motion attributes are not luminance-defined. The detection of first and second-order motion is thought to be mediated by different mechanisms. Here, we compare the ability of Parkinson's disease patients (PDPs) to detect first-order/second-order motion with normal subjects. Subjects had to discriminate the drift direction of first-order motion (luminance-modulated noise) and a second-order motion pattern (named as noise base motion) over a range of stimulus speeds and strengths. Results show that the first-order motion detection deficits could only be seen with lower motion strengths suggesting a ceiling effect with higher motion strengths. However, second order motion detection deficits were seen across high and low motion strengths, suggesting that the second order motion detection may be more affected in PD than the first-order motion detection. Our results indicate that higher-level visual cortex plays an important role in PD patients' disabilities in motion perception.


Off-pump coronary bypass grafting is safe and efficient in patients with left main disease and higher EuroScore.
Summary Left main disease (LMD) and associated cardiac risk factors are often perceived as a limiting factor for the outcome of off-pump coronary artery bypass (OPCAB) grafting. In this study, we assess whether the outcome of OPCAB surgery is affected in such patients. We retrospectively compared perioperative parameters in 66 OPCAB patients (group A) with LMD and 216 OPCAB patients without (group B) LMD. The patients were operated in the time frame between 2002 and 2007. LMD was defined as a stenosis >50%. Patients in group A had a higher EuroSCORE (logistic: 3.7+/-0.1 vs 6.3+/-0.3, p=0.027), increased coronary artery disease (CAD) family history (p=0.015) and cerebrovascular accidents (p=0.027), increased history of congestive heart failure (p=0.013), more urgent surgery (p=0.008), previous percutaneous transluminal coronary angioplasties (PTCAs) (p=0.05) and previous stent implantation (p=0.023). An intra-aortic balloon pump (IABP) was inserted more frequently in the LMD group preoperatively (p=0.004). There were two conversions to on-pump during OPCAB surgery. There were no differences in the postoperative outcomes in the LMD group A versus group B, such as cardiac-related events, neurological deficits, cardiac enzyme course, arrhythmias, blood loss, infections and renal failure. The presence of LMD and higher EuroSCORE does not yield adverse outcomes in OPCAB patients.


An inertia enhanced passive pumping mechanism for fluid flow in microfluidic devices.
We describe and characterize a pumping mechanism that leverages the momentum present in small droplets ejected from a micro-nozzle to drive flow in an open microfluidic device. This approach allows driving flow in a microfluidic device in a regime that offers unique features different to those achievable with typical passive pumping or syringe-pump driven flow. Two flow regimes with specific flow characteristics are described: inertia enhanced passive pumping, in which fluid exchange times in the channel are significantly reduced, and inertia actuated flow, in which it is possible to initiate flow in an empty channel or against natural pressure gradients. Momentum is leveraged to create rapid fluid exchanges, instantaneous flow reversal, filling and mixing inside the microfluidic device.


Declining incidence and mortality of stroke?
The incidence and mortality from stroke in Espoo-Kauniainen, Finland, in 1972-73 were compared to the incidence and mortality from stroke in the same area 1978-80. The factors at the acute stage influencing case fatality were also analyzed. A declining trend in age-adjusted incidence of stroke was observed, though failing to reach statistical significance. The greatest decline was seen in the incidence of cerebral hemorrhage in men, with a statistically significant difference. The incidence of subarachnoid hemorrhage also decreased, and in women the decline was significant. There was no decrease at all of the incidence of cerebral infarction. The total mortality displayed no clear declining trend. However, the mortality from cerebral hemorrhage after three months from stroke had gone down from 72% to 59%. The most important factors responsible for increased case fatality were: lowered level of consciousness, cerebral hemorrhage and old age. The case fatality was also higher for women than for men. Previous heart diseases increased the mortality, but hypertension, diabetes, pure myocardial infarction and previous transient ischaemic attacks had no influence on mortality. The cause of decline in the incidence of cerebral hemorrhage might be improved care of hypertension: the decline in the incidence of subarachnoid hemorrhage however remains unclear.


Patient expectations of fair complaint handling in hospitals: empirical data.
A common finding in several studies is patients' dissatisfaction with complaint handling in health care. The reasons why are for the greater part unknown. The key to an answer may be found in a better understanding of patients' expectations. We investigated patients' expectations of complaint handling in hospitals. Subjects were patients who had lodged a complaint at the complaint committees of 74 hospitals in the Netherlands. A total of 424 patients (response 75%) completed a written questionnaire at the start of the complaint procedures. Derived from justice theory, we asked what they expected from fair procedures, fair communication and fair outcome of complaint handling. The predominant reason for complainants to lodge a complaint was to prevent the incident from happening again. Complainants expected fair procedures from the complaint committee, in particular an impartial position. This was most important to 87% of the complainants. They also expected to be treated respectfully. Furthermore, they expected the hospital and the professional involved to respond to their complaint. A change in hospital performances was the most wanted outcome of complaint handling, according to 79% of the complainants. They also expected disclosure from the professionals. Professionals should admit a mistake when it had occurred. More complainants (65%) considered it most important to get an explanation than an apology (41%). Only 32% of complainants expected the professional to make an effort to restore the doctor-patient relationship. A minority of complainants (7%) wanted financial compensation. Nearly all complainants want to prevent the incident from happening again, not out of pure altruism, but in order to restore their sense of justice. We conclude that complaint handling that does not allow for change is unlikely to meet patients' expectations. Secondly, complaint handling should not be left exclusively to complaint committees, the responses of hospital and professionals are indispensable.


Fibronectin matrix as a scaffold for procollagen proteinase binding and collagen processing.
The extracellular matrix (ECM) proteins fibronectin (FN) and type I collagen (collagen I) are codistributed in many tissues, and collagens have been shown to depend on an FN matrix for fibrillogenesis. Microscopic analysis of a fibroblast ECM showed colocalization of procollagen I with FN fibrils, and proteolytic cleavage of procollagen to initiate fibril formation was significantly reduced with inhibition of FN matrix assembly. We examined the role of FN matrix in procollagen processing by the C-propeptide proteinase bone morphogenetic protein 1 (BMP-1). We found that BMP-1 binds to a cell-assembled ECM in a dose-dependent manner and that, like procollagen, BMP-1 colocalizes with FN fibrils in the matrix microenvironment. Binding studies with FN fragments identified a binding site in FN's primary heparin-binding domain. In solution, BMP-1-FN interactions and BMP-1 cleavage of procollagen I were both enhanced by the presence of heparin, suggesting a role for heparin in complex formation during proteolysis. Indeed, addition of heparin enhanced the rate of procollagen cleavage by matrix-bound BMP-1. Our results show that matrix localization of this proteinase facilitates the initiation of collagen assembly and suggest a model in which FN matrix and associated heparan sulfate act as a scaffold to organize enzyme and substrate for procollagen processing.


Habitat structural complexity mediates the foraging success of multiple predator species.
We investigated the role of freshwater macrophytes as refuge by testing the hypothesis that predators capture fewer prey in more dense and structurally complex habitats. We also tested the hypothesis that habitat structure not only affects the prey-capture success of a single predator in isolation, but also the effectiveness of two predators combined, particularly if it mediates interactions between the predators. We conducted a fully crossed four-factorial laboratory experiment using artificial plants to determine the separate quantitative (density) and qualitative (shape) components of macrophyte structure on the prey-capture success of a predatory damselfly, Ischnura heterosticta tasmanica, and the southern pygmy perch, Nannoperca australis. Contrary to our expectations, macrophyte density had no effect on the prey-capture success of either predator, but both predators were significantly less effective in the structurally complex Myriophyllum analogue than in the structurally simpler Triglochin and Eleocharis analogues. Furthermore, the greater structural complexity of Myriophyllum amplified the impact of the negative interaction between the predators on prey numbers; the habitat use by damselfly larvae in response to the presence of southern pygmy perch meant they captured less prey in Myriophyllum. These results demonstrate habitat structure can influence multiple predator effects, and support the mechanism of increased prey refuge in more structurally complex macrophytes.


A theoretical and empirical investigation of delayed growth response in the continuous culture of bacteria.
When the growth of bacteria in a chemostat is controlled by limiting the supply of a single essential nutrient, the growth rate is affected both by the concentration of this nutrient in the culture medium and by the amount of time that it takes for the chemical and physiological processes that result in the production of new biomass. Thus, although the uptake of nutrient by cells is an essentially instantaneous process, the addition of new biomass is delayed by the amount of time that it takes to metabolize the nutrient. Mathematical models that incorporate this "delayed growth response" (DGR) phenomenon have been developed and analysed. However, because they are formulated in terms of parameters that are difficult to measure directly, these models are of limited value to experimentalists. In this paper, we introduce a DGR model that is formulated in terms of measurable parameters. In addition, we provide for this model a complete set of criteria for determining persistence versus extinction of the bacterial culture in the chemostat. Specifically, we show that DGR plays a role in determining persistence versus extinction only under certain ranges of chemostat operating parameters. It is also shown, however, that DGR plays a role in determining the steady-state nutrient and bacteria concentrations in all instances of persistence. The steady state and transient behavior of solutions of our model is found to be in agreement with data that we obtained in growing Escherichia coli 23716 in a chemostat with glucose as a limiting nutrient. One of the theoretical predictions of our model that does not occur in other DGR models is that under certain conditions a large delay in growth response might actually have a positive effect on the bacteria's ability to persist.


High-power lasers for directed-energy applications.
In this article, we review and discuss the research programs at the Naval Research Laboratory (NRL) on high-power lasers for directed-energy (DE) applications in the atmosphere. Physical processes affecting propagation include absorption/scattering, turbulence, and thermal blooming. The power levels needed for DE applications require combining a number of lasers. In atmospheric turbulence, there is a maximum intensity that can be placed on a target that is independent of the initial beam spot size and laser beam quality. By combining a number of kW-class fiber lasers, scientists at the NRL have successfully demonstrated high-power laser propagation in a turbulent atmosphere and wireless recharging. In the NRL experiments, four incoherently combined fiber lasers having a total power of 5 kW were propagated to a target 3.2 km away. These successful high-power experiments in a realistic atmosphere formed the basis of the Navy's Laser Weapon System. We compare the propagation characteristics of coherently and incoherently combined beams without adaptive optics. There is little difference in the energy on target between coherently and incoherently combined laser beams for multi-km propagation ranges and moderate to high levels of turbulence. Unlike incoherent combining, coherent combining places severe constraints on the individual lasers. These include the requirement of narrow power spectral linewidths in order to have long coherence times as well as polarization alignment of all the lasers. These requirements are extremely difficult for high-power lasers.


Reliability of classification of cerebral palsy in low-birthweight children in four countries.
The reliability of classification of cerebral palsy (CP) in low-birthweight children was assessed by using clinical and research study records sampled from population-based cohort studies in the USA, The Netherlands, Canada, and Germany. Records of neurological examination findings and functional motor assessments were submitted to up to five pediatricians with expertise in CP diagnosis, who grouped children into categories referred to as 'disabling' CP, 'non-disabling' CP, and no CP. Each study provided between 31 and 51 records of children assessed between 2 and 8 years of age, approximately equally divided among the three groupings. The discrimination between 'any CP' and 'no CP' was only fair (mean Kappa coefficients 0.37 to 0.69). However, when more detailed information describing motor function was used, children with 'disabling' CP could be distinguished, on the basis of records, from those without CP or with 'non-disabling' CP with good to excellent reliability (mean Kappa coefficients 0.69 to 0.88). Because of the substantially higher agreement observed when these functional distinctions are made, we recommend that reports or comparisons of rates of CP should include levels of motor function of children with CP, and not simply total CP, among the outcomes of interest.


Relapse patterns in pediatric embryonal central nervous system tumors.
Embryonal tumors of the central nervous system (CNS) share histological features and were therefore initially grouped as primitive neuroectodermal tumors (PNET) and treated similarly. We sought to determine the relapse patterns of specific embryonal CNS tumors. We conducted a historical cohort study of children diagnosed with CNS embryonal tumors from January 2000 to December 2011 in two pediatric neuro-oncology centers. Patients of 21 years of age or younger at time of presentation with a diagnosis of medulloblastoma, supratentorial PNET, pineoblastoma or atypical teratoid/rhabdoid tumor (ATRT) and at least one surveillance MRI were included. A total of 133 patients met inclusion criteria and 49 (37 %) patients relapsed during the observation period. The majority (79 %) of sPNET relapses were local, whereas all (100 %) PB relapses were associated with diffuse leptomeningeal disease. Relapse patterns for MB were more diverse with local recurrence in 27 %, distant recurrence in 35 % and diffuse leptomeningeal disease in 38 %. The frequency of relapses involving the spine differed (p < 0.001) between tumor types (MB 28/55 [51 %], sPNET 3/33 [9 %], ATRT 3/7 [43 %] and PB 12/12 [100 %]). No sPNET patients had isolated spinal relapse (0/14). Embryonal tumors were found to have divergent patterns of recurrence. While medulloblastoma has variable relapse presentations, sPNET relapses locally and pineoblastoma recurs with diffuse leptomeningeal disease involving the spine. These results point toward possibly new upfront treatment stratification among embryonal tumors in accordance with relapse pattern.


A Novel Instrument for Measuring Older People's Attitudes Toward Technology (TechPH): Development and Validation.
The use of health technology by older people is coming increasingly in focus with the demographic changes. Health information technology is generally perceived as an important factor in enabling increased quality of life and reducing the cost of care for this group. Age-appropriate design and facilitation of technology adoption are important to ensure functionality and removal of various barriers to usage. Development of assessment tools and instruments for evaluating older persons' technology adoption and usage as well as measuring the effects of the interventions are of high priority. Both usability and acceptance of a specific technology or service are important factors in evaluating the impact of a health information technology intervention. Psychometric measures are seldom included in evaluations of health technology. However, basic attitudes and sentiments toward technology (eg, technophilia) could be argued to influence both the level of satisfaction with the technology itself as well as the perception of the health intervention outcome. The purpose of this study is to develop a reduced and refined instrument for measuring older people's attitudes and enthusiasm for technology based on relevant existing instruments for measuring technophilia. A requirement of the new instrument is that it should be short and simple to make it usable for evaluation of health technology for older people. Initial items for the TechPH questionnaire were drawn from a content analysis of relevant existing technophilia measure instruments. An exploratory factor analysis was conducted in a random selection of persons aged 65 years or older (N=374) on eight initial items. The scale was reduced to six items, and the internal consistency and reliability of the scale were examined. Further validation was made by a confirmatory factor analysis (CFA). The exploratory factor analysis resulted in two factors. These factors were analyzed and labeled techEnthusiasm and techAnxiety. They demonstrated relatively good internal consistency (Cronbach alpha=.72 and .68, respectively). The factors were confirmed in the CFA and showed good model fit (χ28=21.2, χ2/df=2.65, comparative fit index=0.97, adjusted goodness-of-fit index=0.95, root mean square error of approximation=0.067, standardized root mean square residual=0.036). The construed TechPH score showed expected relations to external real-world criteria, and the two factors showed interesting internal relations. Different technophilia personality traits distinguish clusters with different behaviors of adaptation as well as usage of new technology. Whether there is an independent association with the TechPH score against outcomes in health technology projects needs to be shown in further studies. The instrument must also be validated in different contexts, such as other countries.


The discriminative stimulus effects of the neurotensin NTS1 receptor agonist PD149163 in rats: stimulus generalization testing with dopamine D1 and D2 receptor ligands.
Brain-penetrant neurotensin NTS1 receptor agonists produce antipsychotic drug-like effects in animal models, including inhibition of conditioned avoidance responding and reversal of psychostimulant-induced hyperactivity and stereotypy. Allosteric interactions between NTS1 receptors and dopamine D2 receptors may account for some of these antipsychotic effects. In order to determine the role that dopamine receptors may play in the behavioral effects produced by activation of NTS1 receptors, a drug discrimination approach was used in rats to evaluate the potential mediation of NTS1 receptor agonist stimulus effects by dopamine D1 and D2 receptors. Rats were trained to discriminate either the NTS1 receptor agonist PD149163, the D1 receptor agonist SKF81297, or the D2 receptor agonist quinpirole from vehicle in a two choice drug discrimination task. Full stimulus generalization occurred from PD149163 to the typical antipsychotic drug and D2 receptor-preferring antagonist haloperidol. However, stimulus generalization did not occur from SKF81297 or quinpirole to PD149163. The discriminative cue for SKF91297 and quinpirole was fully blocked the D1 receptor antagonist SCH23390 and the D2/3 receptor antagonist raclopride, respectively. Cross generalization did not occur between SKF91297 and quinpirole. Based on these findings, the stimulus effects of PD149163 may be mediated, in part, through D2 receptor antagonism, but this may only be evident when PD149163 is used as the training drug.


Dietary intake of pregnant adolescents cared for in primary health care units of a Brazilian urban municipality.
to evaluate the adequacy of dietary intake and the anthropometric nutritional status of pregnant adolescents in the city of Niterói, Rio de Janeiro, Brazil. METERIALS AND METHODS: forty-two adolescents (13-19 years of age), with single-fetus gestation, assisted in the public prenatal health care units between 2008-2014, participated in the study. Body mass index (BMI) was used to assess the nutritional status. Dietary intake was assessed by 24h dietary recalls on two days during a week and one during weekend. Basal metabolic rate was measured by indirect calorimetry and used to determine the energy requirements. Mixed effects models were used to assess dietary intake over the gestational weeks (random effect) and BMI. mean age (SD) of the pregnant women was 16.5 (1.5) years and the majority received allowance from a cash transfer federal program. Overall, 30.3% were overweight/obese pre-pregnancy and 16.7%, during pregnancy. Energy and protein intake adequacies decreased with increasing BMI and gestational week. There was adequate dietary intake of energy, protein, vitamin A and zinc and insufficient intakes of iron and calcium. There was excessive intake of sodium. pregnant adolescents living in underprivileged socio-economic environments assisted for prenatal care in primary health care units have adequate intakes of energy, protein, vitamin A and zinc. Pre-pregnancy overweight and high sodium intake are causes of concern due to the future implications for their health. The official Brazilian recommended criterion for anthropometric assessment in pregnancy of adolescents proved to be inadequate.


Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma.
Measurements of plasma methoxytyramine, the O-methylated dopamine metabolite, are useful for detecting rare dopamine-producing pheochromocytomas and paragangliomas (PPGLs) and head and neck paragangliomas (HNPGLs), but utility for screening beyond that achieved using standard measurements of normetanephrine and metanephrine is unclear. Evaluation of the additional utility of methoxytyramine compared to plasma normetanephrine and metanephrine for diagnosis of PPGLs and HNPGLs. Comparative prospective study. Comparison of mass spectrometric-based measurements of plasma methoxytyramine, normetanephrine and metanephrine in 1963 patients tested for PPGLs at six tertiary medical centers according to reference intervals verified in 423 normotensive and hypertensive volunteers. Of the screened patients, 213 had PPGLs and 38 HNPGLs. Using an upper cut-off of 0.10 nmol/L for methoxytyramine, 0.45 nmol/L for metanephrine and age-specific upper cut-offs for normetanephrine, diagnostic sensitivity with the addition of methoxytyramine increased from 97.2% to 98.6% for patients with PPGLs and from 22.1% to 50.0% for patients with HNPGLs, with a small decrease in specificity from 95.9% to 95.1%. Addition of methoxytyramine did not significantly alter areas under receiver operating characteristic curves for patients with PPGLs (0.984 vs 0.991), but did increase (P < 0.05) areas for patients with HNPGLs (0.627 vs 0.801). Addition of methoxytyramine also increased the proportion of patients with PPGLs who showed highly positive predictive elevations of multiple metabolites (70.9% vs 49.3%). While the benefit of additional measurements of plasma methoxytyramine for the detection of PPGLs is modest, the measurements do assist with positive confirmation of disease and are useful for the detection of HNPGLs.


Comparison of the intraarticular effectiveness of triamcinolone hexacetonide and triamcinolone acetonide in treatment of juvenile rheumatoid arthritis.
To compare patients with juvenile rheumatoid arthritis (JRA) injected with triamcinolone hexacetonide (TH) or triamcinolone acetonide (TA) with respect to time to relapse. This was a retrospective chart review of 85 patients: 51 patients with JRA who had received a joint injection with TH during the period June 2000-April 2001 and 48 patients who had received a joint injection with TA during the period May 2001-March 2002 who were followed for a minimum of 15 months, after an intraarticular steroid injection. The primary endpoint variable for the study was the time to relapse of the arthritis in the affected joint following an intraarticular injection. A total of 227 joints were injected, 114 with TH and 113 with TA. In the TH group the mean time to relapse (+/- SE) was 10.14 +/- 0.49 months compared to the TA group at 7.75 +/- 0.49 months (p < 0.0001) using the log-rank test. A proportional hazards (Cox) regression analysis revealed no statistical association between sex, duration of illness, or type of arthritis and relapse time. An analysis was performed on the first intraarticular injection for each patient, with the average time to relapse for all joints injected of 10.36 +/- 0.72 months for TH compared to 8.45 +/- 0.78 months for TA (p < 0.02). A further analysis of the first knee injections showed a relapse time in the TH group of 11.11 +/- 0.81 months compared to 7.95 +/- 0.95 months for TA (p < 0.008). TH offers an advantage to TA, as there is a longer duration of action leading to an improved prolonged response rate in weight-bearing joints, particularly the knees. The results suggest that TH should be the intraarticular steroid of choice, particularly for the knee joint, in patients with JRA.


WIPI1 is a conserved mediator of right ventricular failure.
Right ventricular dysfunction is highly prevalent across cardiopulmonary diseases and independently predicts death in both heart failure (HF) and pulmonary hypertension (PH). Progression towards right ventricular failure (RVF) can occur in spite of optimal medical treatment of HF or PH, highlighting current insufficient understanding of RVF molecular pathophysiology. To identify molecular mechanisms that may distinctly underlie RVF, we investigated the cardiac ventricular transcriptome of advanced HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, we identified an RVF-specific gene module, for which WIPI1 served as a hub and HSPB6 and MAP4 as drivers, and confirmed the ventricular specificity of Wipi1, Hspb6, and Map4 transcriptional changes in adult murine models of pressure overload induced RV- versus LV- failure. We uncovered a shift towards non-canonical autophagy in the failing RV that correlated with RV-specific Wipi1 upregulation. In vitro siRNA silencing of Wipi1 in neonatal rat ventricular myocytes limited non-canonical autophagy and blunted aldosterone-induced mitochondrial superoxide levels. Our findings suggest that Wipi1 regulates mitochondrial oxidative signaling and non-canonical autophagy in cardiac myocytes. Together with our human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render Wipi1 a potential target for RV-directed HF therapy.


Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo.
Hyperphosphorylated forms of the microtubule-associated protein (MAP) tau accumulate in Alzheimer's disease and related tauopathies and are thought to have an important role in neurodegeneration. However, the mechanisms through which phosphorylated tau induces neurodegeneration have remained elusive. Here, we show that tau-induced neurodegeneration is associated with accumulation of filamentous actin (F-actin) and the formation of actin-rich rods in Drosophila and mouse models of tauopathy. Importantly, modulating F-actin levels genetically leads to dramatic modification of tau-induced neurodegeneration. The ability of tau to interact with F-actin in vivo and in vitro provides a molecular mechanism for the observed phenotypes. Finally, we show that the Alzheimer's disease-linked human beta-amyloid protein (Abeta) synergistically enhances the ability of wild-type tau to promote alterations in the actin cytoskeleton and neurodegeneration. These findings raise the possibility that a direct interaction between tau and actin may be a critical mediator of tau-induced neurotoxicity in Alzheimer's disease and related disorders.


Electroorganic Synthesis under Flow Conditions.
Despite the long history of electroorganic synthesis, it did not participate in the mainstream of chemical research for a long time. This is probably due to the lack of equipment and standardized protocols. However, nowadays organic electrochemistry is witnessing a renaissance, and a wide range of interesting electrochemical transformations and methodologies have been developed, not only for academic purposes but also for large scale industrial production. Depending on the source of electricity, electrochemical methods can be inherently green and environmentally benign and can be easily controlled to achieve high levels of selectivity. In addition, the generation and consumption of reactive or unstable intermediates and hazardous reagents can be achieved in a safe way. Limitations of traditional batch-type electrochemical methods such as the restricted electrode surface, the necessity of supporting electrolytes, and the difficulties in scaling up can be alleviated using electrochemical flow cells. Microreactors offer high surface-to-volume ratios and enable precise control over temperature, residence time, flow rate, and pressure. In addition, efficient mixing, enhanced mass and heat transfer, and handling of small volumes lead to simpler scaling-up protocols and minimize safety concerns. Electrolysis under flow conditions reduces the possibility of overoxidation as the reaction mixture is flown continuously out of the reactor in contrast to traditional batch-type electrolysis cells. In this Account, we highlight our contributions in the area of electroorganic synthesis under flow conditions over the past decade. We have designed and manufactured different generations of electrochemical flow cells. The first-generation reactor was effectively used in developing a simple one-step synthesis of diaryliodonium salts and used in proof-of-concept reactions such as the trifluoromethylation of electron-deficient alkenes via Kolbe electrolysis of trifluoroacetic acid in addition to the selective deprotection of the isonicotinyloxycarbonyl (iNoc) group from carbonates and thiocarbonates. The improved second-generation flow cell enabled the development of efficient synthesis of isoindolinones, benzothiazoles, and thiazolopyridines, achieving gram-scale for some of the products easily without changing the reactor design or reoptimizing the reaction parameters. In addition, the same reactor was used in the development of an efficient continuous flow electrochemical synthesis of hypervalent iodine reagents. The generated unstable hypervalent iodine reagents were easily used without isolation in various oxidative transformations in a coupled flow/flow manner and could be easily transformed into bench-stable reagents via quantitative ligand exchange with the appropriate acids. Our second-generation reactor was further improved and commercialized by Vapourtec Ltd. We have demonstrated the power of online analysis in accelerating optimizations and methodology development. Online mass spectrometry enabled fast screening of the charge needed for the cyclization of amides to isoindolinones. The power of online 2D-HPLC combined with a Design of Experiments approach empowered the rapid optimization of stereoselective electrochemical alkoxylations of amino acid derivatives.


Altered adipocyte structure and function in nutritionally programmed microswine offspring.
Adipose tissue (AT) dysfunction links obesity of any cause with cardiometabolic disease, but whether early-life nutritional deficiency can program adipocyte dysfunction independently of obesity is untested. In 3-5-month-old juvenile microswine offspring exposed to isocaloric perinatal maternal protein restriction (MPR) and exhibiting accelerated prepubertal fat accrual without obesity, we assessed markers of acquired obesity: adiponectin and tumor necrosis factor (TNF)-α messenger ribonucleic acid (mRNA) levels and adipocyte size in intra-abdominal (ABD-AT) and subcutaneous (SC-AT) adipose tissues. Plasma cortisol, leptin and insulin levels were measured in fetal, neonatal and juvenile offspring. In juvenile low-protein offspring (LPO), adipocyte size in ABD-AT was reduced 22% (P = 0.011 v. controls), whereas adipocyte size in SC-AT was increased in female LPO (P = 0.05) and normal in male LPO; yet, adiponectin mRNA in LPO was low in both sexes and in both depots (P < 0.001). Plasma leptin (P = 0.004) and cortisol (P < 0.05) were reduced only in neonatal LPO during MPR. In juveniles, correlations between % body fat and adiponectin mRNA, TNF-α mRNA or plasma leptin were significant in normal-protein offspring (NPO) but absent in LPO. Plasma glucose in juvenile LPO was increased in males but decreased in females (interaction, P = 0.023); plasma insulin levels and insulin sensitivity were unaffected. Findings support nutritional programming of adipocyte size and gene expression and subtly altered glucose homeostasis. Reduced adiponectin mRNA and adipokine dysregulation in juvenile LPO following accelerated growth occurred independently of obesity, adipocyte hypertrophy or inflammatory markers; thus, perinatal MPR and/or growth acceleration can alter adipocyte structure and disturb adipokine homeostasis in metabolically adverse patterns predictive of enhanced disease risk.


Conventional chest physiotherapy compared to other airway clearance techniques for cystic fibrosis.
Cystic fibrosis is an inherited life-limiting disorder, characterised by pulmonary infections and thick airway secretions. Chest physiotherapy has been integral to clinical management in facilitating removal of airway secretions. Conventional chest physiotherapy techniques (CCPT) have depended upon assistance during treatments, while more contemporary airway clearance techniques are self-administered, facilitating independence and flexibility. To compare CCPT with other airway clearance techniques in terms of their effects on respiratory function, individual preference, adherence, quality of life and other outcomes. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched CINAHL from 1982 to 2002 and AMED from 1985 to 2002. Date of most recent search: January 2004. Randomised or quasi-randomised clinical trials including those with a cross-over design where CCPT was compared with other airway clearance techniques. Studies of less than seven days duration were excluded. Two reviewers allocated quality scores to relevant studies and independently extracted data. If we were unable to extract data, we invited authors to submit their data. We excluded studies from meta-analysis when data were lost or study design precluded comparison. For some continuous outcomes, we used the generic inverse variance method for meta-analysis of data from cross-over trials and data from parallel-designed trials were incorporated for comparison. We also examined efficacy of specific techniques and effects of treatment duration. Seventy-eight publications were identified by the searches. Twenty-nine of these were included, representing 15 data sets with 475 participants. There was no difference between CCPT and other airway clearance techniques in terms of respiratory function measured by standard lung function tests. Studies undertaken during acute exacerbations demonstrated relatively large gains in respiratory function irrespective of airway clearance technique. Longer-term studies demonstrated smaller improvements or deterioration over time. Ten studies reported individual preferences for technique, with participants tending to favour self-administered techniques. Heterogeneity in the measurement of preference precluded these data from meta-analysis. This review demonstrated no advantage of CCPT over other airway clearance techniques in terms of respiratory function. There was a trend for participants to prefer self-administered airway clearance techniques. Limitations of this review included a paucity of well-designed, adequately-powered, long-term trials.


Spaced learning enhances subsequent recognition memory by reducing neural repetition suppression.
Spaced learning usually leads to better recognition memory as compared with massed learning, yet the underlying neural mechanisms remain elusive. One open question is whether the spacing effect is achieved by reducing neural repetition suppression. In this fMRI study, participants were scanned while intentionally memorizing 120 novel faces, half under the massed learning condition (i.e., four consecutive repetitions with jittered interstimulus interval) and the other half under the spaced learning condition (i.e., the four repetitions were interleaved). Recognition memory tests afterward revealed a significant spacing effect: Participants recognized more items learned under the spaced learning condition than under the massed learning condition. Successful face memory encoding was associated with stronger activation in the bilateral fusiform gyrus, which showed a significant repetition suppression effect modulated by subsequent memory status and spaced learning. Specifically, remembered faces showed smaller repetition suppression than forgotten faces under both learning conditions, and spaced learning significantly reduced repetition suppression. These results suggest that spaced learning enhances recognition memory by reducing neural repetition suppression.


Evaluation of the similarity of gene expression data estimated with SAGE and Affymetrix GeneChips.
Serial Analysis of Gene Expression (SAGE) and microarrays have found a widespread application, but much ambiguity exists regarding the evaluation of these technologies. Cross-platform utilization of gene expression data from the SAGE and microarray technology could reduce the need for duplicate experiments and facilitate a more extensive exchange of data within the research community. This requires a measure for the correspondence of the different gene expression platforms. To date, a number of cross-platform evaluations (including a few studies using SAGE and Affymetrix GeneChips) have been conducted showing a variable, but overall low, concordance. This study evaluates these overall measures and introduces the between-ratio difference as a concordance measure pergene. In this study, gene expression measurements of Unigene clusters represented by both Affymetrix GeneChips HG-U133A and SAGE were compared using two independent RNA samples. After matching of the data sets the final comparison contains a small data set of 1094 unique Unigene clusters, which is unbiased with respect to expression level. Different overall correlation approaches, like Up/Down classification, contingency tables and correlation coefficients were used to compare both platforms. In addition, we introduce a novel approach to compare two platforms based on the calculation of differences between expression ratios observed in each platform for each individual transcript. This approach results in a concordance measure per gene (with statistical probability value), as opposed to the commonly used overall concordance measures between platforms. We can conclude that intra-platform correlations are generally good, but that overall agreement between the two platforms is modest. This might be due to the binomially distributed sampling variation in SAGE tag counts, SAGE annotation errors and the intensity variation between probe sets of a single gene in Affymetrix GeneChips. We cannot identify or advice which platform performs better since both have their (dis)-advantages. Therefore it is strongly recommended to perform follow-up studies of interesting genes using additional techniques. The newly introduced between-ratio difference is a filtering-independent measure for between-platform concordance. Moreover, the between-ratio difference per gene can be used to detect transcripts with similar regulation on both platforms.


Using "Omics" and Integrated Multi-Omics Approaches to Guide Probiotic Selection to Mitigate Chytridiomycosis and Other Emerging Infectious Diseases.
Emerging infectious diseases in wildlife are responsible for massive population declines. In amphibians, chytridiomycosis caused by Batrachochytrium dendrobatidis, Bd, has severely affected many amphibian populations and species around the world. One promising management strategy is probiotic bioaugmentation of antifungal bacteria on amphibian skin. In vivo experimental trials using bioaugmentation strategies have had mixed results, and therefore a more informed strategy is needed to select successful probiotic candidates. Metagenomic, transcriptomic, and metabolomic methods, colloquially called "omics," are approaches that can better inform probiotic selection and optimize selection protocols. The integration of multiple omic data using bioinformatic and statistical tools and in silico models that link bacterial community structure with bacterial defensive function can allow the identification of species involved in pathogen inhibition. We recommend using 16S rRNA gene amplicon sequencing and methods such as indicator species analysis, the Kolmogorov-Smirnov Measure, and co-occurrence networks to identify bacteria that are associated with pathogen resistance in field surveys and experimental trials. In addition to 16S amplicon sequencing, we recommend approaches that give insight into symbiont function such as shotgun metagenomics, metatranscriptomics, or metabolomics to maximize the probability of finding effective probiotic candidates, which can then be isolated in culture and tested in persistence and clinical trials. An effective mitigation strategy to ameliorate chytridiomycosis and other emerging infectious diseases is necessary; the advancement of omic methods and the integration of multiple omic data provide a promising avenue toward conservation of imperiled species.


Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma.
Severe traumatic brain injury (TBI) has a major role in mortality rate among the other types of trauma. The aim of this clinical study was to assess the effect of progesterone on the improvement of neurologic outcome in patients with acute severe TBI. A total of 76 patients who had arrived within 8h of injury with a Glasgow Coma Score≤8 were enrolled in the study. In a randomized style 38 received progesterone (1mg/kg per 12h for 5 days) and 38 did not. There was a better recovery rate and GOS score for the patients who were given progesterone than for those in the control group in a 3-months follow-up period (50% vs. 21%); subgroup analysis showed a significant difference in the percentage of favorable outcome between the two groups with GCS of 5-8 (p=0.03). The use of progesterone may significantly improve neurologic outcome of patients suffering severe TBI up to 3 months after injury, especially those with 5≤GCS≤8, providing a potential benefit to the treatment of acute severe TBI patients. Considering this drug had no significant side effects, so progesterone could be used in patients with severe TBI as a neuro-protective drug.


Dok-4 regulates GDNF-dependent neurite outgrowth through downstream activation of Rap1 and mitogen-activated protein kinase.
During development of the central and peripheral nervous systems, neurite extension mediated via glial-cell-line-derived neurotrophic factor (GDNF) and its receptor RET is critical for neuronal differentiation. In the present study, we investigated the role of the RET substrate Dok-4 in neurite outgrowth induced by the GDNF/RET signaling pathway. In TGW neuroblastoma cells, which endogenously express both RET and Dok-4, depletion of Dok-4 through treatment with small interfering RNA resulted in a marked decrease in GDNF-stimulated neurite outgrowth. By contrast, exogenous expression of wild-type Dok-4 induced sustained p44/42 mitogen-activated protein kinase (ERK1/2) activation and enhanced neurite outgrowth. Expression of Dok-4 mutants in which the tyrosine residues at codons 187, 220 and 270, conserved between Dok-4, -5, and -6, were each replaced with a phenylalanine inhibited sustained ERK1/2 activation and neurite outgrowth. We also found that Dok-4 induced a significant activation of the small G protein Rap1 and that expression of a dominant active Rap1 mutant restored neurite outgrowth in Dok-4-depleted cells. By contrast, expression of a dominant negative Rap1 mutant impaired GDNF-stimulated neurite outgrowth from TGW cells. Finally, we found that neurite formation in cultured rat hippocampal neurons was enhanced by the expression of Dok-4. Together, our results suggest that Dok-4, through activation of the Rap1-ERK1/2 pathway, regulates GDNF-mediated neurite outgrowth during neuronal development.


Ldb1 Is Essential for the Development of Isthmic Organizer and Midbrain Dopaminergic Neurons.
LIM domain-binding protein 1 (Ldb1) is a nuclear cofactor that interacts with LIM homeodomain proteins to form multiprotein complexes that are important for transcription regulation. Ldb1 has been shown to play essential roles in various processes during mouse embryogenesis. To determine the role of Ldb1 in mid- and hindbrain development, we have generated a conditional mutant with a specific deletion of the Ldb1 in the Engrailed-1-expressing region of the developing mid- and hindbrain. Our study showed that the deletion impaired the expression of signaling molecules, such as fibroblast growth factor 8 (FGF8) and Wnt1, in the isthmic organizer and the expression of Shh in the ventral midbrain. The midbrain and the cerebellum were severely reduced in size, and the midbrain dopaminergic (mDA) neurons were missing in the mutant. These defects are identical to the phenotype that has been observed previously in mice with a deletion of the LIM homeodomain gene Lmx1b. Our results thus provide genetic evidence supporting that Ldb1 and Lmx1b function cooperatively to regulate mid- and hindbrain development. In addition, we found that mouse embryonic stem cells lacking Ldb1 failed to generate several types of differentiated neurons, including the mDA neurons, serotonergic neurons, cholinergic neurons, and olfactory bulb neurons, indicating an essential cell-autonomous role for Ldb1 in the development of these neurons.


Recent applications in natural product synthesis of dihydrofuran and -pyran formation by ring-closing alkene metathesis.
In the past two decades, alkene metathesis has risen in prominence to become a significant synthetic strategy for alkene formation. Many total syntheses of natural products have used this transformation. We review the use, from 2003 to 2015, of ring-closing alkene metathesis (RCM) for the generation of dihydrofurans or -pyrans in natural product synthesis. The strategies used to assemble the RCM precursors and the subsequent use of the newly formed unsaturation will also be highlighted and placed in context.


A Typology of Patients Based on Decision-Making Styles: Cross-Sectional Survey Study.
Although previous research shows broad differences in the impact of online health information on patient-practitioner decision making, specific research is required to identify and conceptualize patient decision-making styles related to the use of online health information and to differentiate segments according to the influence of online information on patient decision making and interactions with health professionals. This study aimed to investigate patients' decision making in relation to online health information and interactions with health care practitioners. We also aimed to present a typology of patients based on significant differences in their decision making. We applied a large-scale cross-sectional research design using a survey. Data, generated using a questionnaire that was administered by companies specializing in providing online panels, were collected from random samples of baby boomers in the United Kingdom, the United States, and New Zealand. The total sample comprised 996 baby boomers born between 1946 and 1964, who had used the internet in the previous 6 months to search for and share health-related information. Data were analyzed using hierarchical cluster analysis and confirmatory factor analysis, as well as one-way analysis of variance, chi-square tests, and paired sample t tests. Analyses identified 3 key decision-making styles that served as the base for 4 unique and stable segments of patients with distinctive decision-making styles: the Collaborators (229/996, 23.0%), the Autonomous-Collaborators (385/996, 38.7%), the Assertive-Collaborators (111/996, 11.1%), and the Passives (271/996, 27.2%). Profiles were further developed for these segments according to key differences in the online health information behavior, demographics, and interactional behaviors of patients. The typology demonstrates that collaborative decision making is dominant among patients either in its pure form or in combination with autonomous or assertive decision making. In other words, most patients (725/996, 72.8%) show significant collaboration in their decision making with health care professionals. However, at times, patients in the combination Autonomous-Collaborative segment prefer to exercise individual autonomy in their decision making, and those in the combination Assertive-Collaborative segment prefer to be assertive with health professionals. Finally, this study shows that a substantial number of patients adopt a distinctly passive decision-making style (271/996, 27.2%). The patient typology provides a framework for distinguishing practice-relevant and addressable segments with important implications for health care practitioners, including better-targeted communication programs for patients and more successful outcomes for health care services in the long term.


Prenatal testosterone exposure as a model for the study of endocrine-disrupting chemicals on the gerbil prostate.
The development of the prostate depends on a precise androgenic control, so sensible interferences may predispose this gland to develop prostatic diseases during life. These aspects are of interest and preoccupation, since human beings are exposed to a growing number of endocrine-disrupting chemicals with androgenic potential. Therefore, our aim was to evaluate the prostates of adult gerbils exposed to testosterone during intrauterine life. Serological, morphological, morphometric-stereologic, immunohistochemical and three-dimensional reconstruction analyses were used. We found that the testosterone effects were dose-dependent and more harmful to females, leading to the development of masculine characteristics, evidenced by an increased anogenital distance, and absence of vaginal opening and the ectopic development of prostatic tissue. Moreover, premalignant lesions, such as prostatic intraepithelial neoplasia, were observed in addition to inflammatory foci in the prostate. The results showed that the prenatal exposure to testosterone may affect the reproductive system, disrupting developmental processes and increasing susceptibility to the development of prostatic diseases in the Mongolian gerbil.


[Oncolytic virus therapy for malignant brain tumors].
Oncolytic viruses are genetically engineered, recombinant viruses or naturally occurring, attenuated viruses that infect, replicate selectively within, and destroy tumor cells. These viruses are nontoxic to normal tissues, and progeny viruses released from destroyed tumor cells can spread and infect surrounding tumor cells. In addition, most oncolytic viruses can elicit specific antitumor immunity in the course of tumor cell destruction. Currently, the main route of virus administration is direct intratumoral injection that enables maximum virus delivery to tumor cells and minimum systemic adverse events. Several types of oncolytic viruses have been tested in clinical trials for recurrent malignant glioma, among which genetically engineered herpes simplex viruses type 1 seems to be the most promising because of its high tumor selectivity (indicating safety) and potency (indicating efficacy). Oncolytic virus therapy has been developed for various types of cancers other than glioma, including malignant melanoma and prostate, breast, head & neck and colon cancers. Thus far, oncolytic viruses that are inoculated intratumorally, are shown to be safe; adverse events typically observed are usually transient and include local inflammation and flu-like symptoms. Oncolytic viruses can be used in combination with chemotherapy or other conventional therapies, which, in some cases, can lead to synergistic effects. This review summarizes the recent advances in clinical and preclinical research on oncolytic virus therapy for malignant brain tumors.


Thin-film epidural microelectrode arrays for somatosensory and motor cortex mapping in rat.
Assessments of somatosensory and motor cortical somatotopy in vivo can provide important information on sensorimotor physiology. Here, novel polyimide-based thin-film microelectrode arrays (72 contacts) implanted epidurally, were used for recording of somatosensory evoked potentials (SEPs) and somatosensory cortex somatotopic maps of the rat. The objective was to evaluate this method with respect to precision and reliability. SEPs and somatosensory maps were measured twice within one session and again after 8 days of rest. Additionally, motor cortex maps were acquired once to assess the spatial relationship between somatosensory and motor representations of fore- and hindlimb within one individual. Somatosensory maps were well reproduced within and between sessions. SEP amplitudes and latencies were highly reliable within one recording session (combined intraclass correlation 90.5%), but less so between sessions (21.0%). Somatosensory map geometry was stable within and between sessions. For the forelimb the somatosensory representation had a 30% overlap with the corresponding motor area. No significant overlap was found for the hindlimb. No evidence for cortical injury was found on histology (Nissl). Thin-film epidural electrode array technology enables a detailed assessment of sensorimotor cortex physiology in vivo and can be used in longitudinal designs enabling studies of learning and plasticity processes.


Pattern of nursing interventions performed on trauma victims according to the Nursing Activities Score.
Objective To identify the pattern of nursing interventions performed on trauma victims in the Intensive Care Unit (ICU). Method Prospective study performed in the ICU of a hospital in São Paulo, Brazil. Nursing interventions were identified using the Nursing Activities Score (NAS). Results The sample consisted of 200 patients, most of them male, with a mean age of 40.7, victims of transport accidents. The NAS mean was 71.3%. The pattern of nursing interventions identified included monitoring and titration, laboratory investigations, medication (with the exception of vasoactive drugs), hygiene procedures, caring for drains, mobilization and positioning, support and care of relatives and patient, administrative and managerial tasks, respiratory support, care of artificial airways, treatment for improving lung function, and quantitative urine output measurement. The monitoring and mobilization interventions required care beyond what is normally required by ICU patients. Conclusion The results of this study provide important contributions to plan training activities and to size ICU nursing team.


Sexual Dimorphism of Maxillary Sinus: A Morphometric Analysis using Cone Beam Computed Tomography.
Age and sex determination in forensic sciences are primary components of any skeletal analysis. As most bones used for sex determination are recovered in incomplete state, it is often necessary to use bones that are recovered intact e.g., the maxillary sinus. Cone Beam Computed Tomography (CBCT) can provide precise information about complex anatomical structures, as it is characterized by rapid volumetric image acquisition with high resolution. The present study was designed to evaluate the size and volume of Maxillary Sinus (MS) in determining gender by CBCT. Bilateral maxillary sinus images (left and right) were acquired for 100 patients (50 females and 50 males) and different parameters (width, length, height, area, perimeter and volume) were measured and evaluated. Mean and standard deviation of both maxillary sinuses measurements were calculated and compared. The data was subjected to discriminative statistical analysis and analysed using unpaired t-test. Comparison between male and female groups showed statistically insignificant differences on both the right and left sides with respect to the maxillary sinus length, height, area, volume and perimeter. However, the female group showed statistically significant higher values for left side MS width (p=0.041) and left side MS width can be used to determine gender with an overall accuracy of 60%. The final result of discriminative analysis shows that the ability of the maxillary sinus to identify gender was 68% in males and 74% in females with an overall accuracy of 71%. Maxillary sinus width can be used as an aid in forensic anthropology for gender determination.


Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus erythematosus.
To compare the incidence and extent of coronary artery calcification (CAC) as measured by electron beam computed tomography (EBCT) in patients with systemic lupus erythematosus (SLE) and controls, and to identify variables associated with CAC in patients with SLE. Female patients with SLE and matched controls were recruited; EBCT of the coronary arteries was performed, and laboratory values (including the homocysteine concentration, the lipid level, the high-sensitivity C-reactive protein [hsCRP] concentration, the glomerular filtration rate [GFR], and the level of soluble CD154 [sCD154]) were determined. For patients, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index and the SLE Disease Activity Index scores were recorded. Tests of association between the CAC score and the above-mentioned variables were performed. The incidence of CAC was higher in patients with SLE than in controls (P = 0.009), and patients had a higher mean raw CAC (rCAC) score (87.9 versus 9.6 in controls; P = 0.02). In particular, more CAC-positive patients than CAC-positive controls had rCAC scores above the 75th percentile (P = 0.003). Among both patients and controls, those with CAC were approximately 10 years older than those without CAC. In addition to age, a significant determinant of positive CAC status in both groups was the number of cardiovascular risk factors. In patients with SLE, CAC was associated with a higher homocysteine concentration, a lower GFR, and longer disease duration. In controls, the total cholesterol level correlated positively with CAC. When multivariate logistic regression methods were applied to candidate explanatory variables, homocysteine concentration, age, and disease duration (but not the levels of sCD154 or hsCRP) contributed significantly to CAC status. The methylenetetrahydrofolate reductase C677T genotype was not a predictor of hyperhomocysteinemia or CAC status. Among patients with SLE, the homocysteine concentration, the GFR, age, and disease duration were associated with CAC. CAC occurred more frequently and was more extensive in patients with SLE than in controls, suggesting that EBCT could be used to detect premature atherosclerosis in the former group. An elevated homocysteine concentration might identify patients with SLE who are likely to have premature atherosclerosis and who would benefit from evaluation of CAC by EBCT.


Factors that influence risky sexual behaviors among men who have sex with men in Liaoning province, China: a structural equation model.
HIV prevalence among men who have sex with men (MSM) has increased rapidly in China. Behavioral and biologic interventions are the key to control the spreading of HIV in the MSM population and the primary strategy for reducing the spread of AIDS in China. The objective of this study is to explore the relationship among HIV-related knowledge, the basic information of respondents, service utilization and risky sexual behavior. Respondent-driven sampling was used to recruit 225 MSM in Fushun and Huludao in China. The results of univariate analysis showed that condom use in the past 6 months was associated with age, being more knowledgeable about HIV, accepting lubricant distribution, and peer education (p<0.05). The structural equation modeling (SEM) results was as following, χ(2)=863.45 (p<0.01); root mean square error of approximation (RMSEA)=0.04; goodness of fit (GFI)=0.94, which indicated the model fitted the data well. The factor loads of HIV-related knowledge, the basic information of respondents, service utilization and risky sexual behavior was -0.06, 0.07, -0.27, respectively, which indicated that service utilization was likely to be a major factor negatively impacting risky sexual behavior. For service utilization, the greatest item load was for distribution of lubricants and peer education, 0.69, 0.68, respectively. The factor load of HIV-related knowledge and service utilization was 0.15, which suggested that risky sexual behaviors might be indirectly reduced by improving HIV/AIDS knowledge to increase service utilization. Basic information (age, income, marital status, age at first sexual intercourse) had a greater impact on service utilization, with a load factor of 0.26. For basic information, the greatest item load was age (0.96). In terms of the intervention strategies, it is essential that public health education is provided for the young, to ultimately decrease risky behaviors in MSM.


Acne: more than skin deep.
Acne is one of the most prevalent skin conditions affecting teenagers. It is a disease of the pilosebaceous unit. Blockage of sebaceous glands and colonisation with Proionobacterium acnes leads to acne. Grading the severity of acne helps to determine the appropriate treatment. Treatment of acne should be started as early as possible to minimise the risk of scarring and adverse psychological effects. It should be tailored to the individual patient, the type of acne, its severity, the patient's ability to use the treatment, and the psychological state. Topical agents are the mainstay for treatment of mild acne. Moderate acne is treated with oral antibiotics. Resistance to antibiotics may be reduced by subsequent use of non-antibiotic topical medications. Severe acne is treated with isotretinoin, and this can lead to permanent remission. With better education and care given by medical profession, acne treatment could be significantly improved.


Toward evidence-based quality improvement. Evidence (and its limitations) of the effectiveness of guideline dissemination and implementation strategies 1966-1998.
To determine effectiveness and costs of different guideline dissemination and implementation strategies. MEDLINE (1966 to 1998), HEALTHSTAR (1975 to 1998), Cochrane Controlled Trial Register (4th edn 1998), EMBASE (1980 to 1998), SIGLE (1980 to 1988), and the specialized register of the Cochrane Effective Practice and Organisation of Care group. Randomized-controlled trials, controlled clinical trials, controlled before and after studies, and interrupted time series evaluating guideline dissemination and implementation strategies targeting medically qualified health care professionals that reported objective measures of provider behavior and/or patient outcome. Two reviewers independently abstracted data on the methodologic quality of the studies, characteristics of study setting, participants, targeted behaviors, and interventions. We derived single estimates of dichotomous process variables (e.g., proportion of patients receiving appropriate treatment) for each study comparison and reported the median and range of effect sizes observed by study group and other quality criteria. We included 309 comparisons derived from 235 studies. The overall quality of the studies was poor. Seventy-three percent of comparisons evaluated multifaceted interventions. Overall, the majority of comparisons (86.6%) observed improvements in care; for example, the median absolute improvement in performance across interventions ranged from 14.1% in 14 cluster-randomized comparisons of reminders, 8.1% in 4 cluster-randomized comparisons of dissemination of educational materials, 7.0% in 5 cluster-randomized comparisons of audit and feedback, and 6.0% in 13 cluster-randomized comparisons of multifaceted interventions involving educational outreach. We found no relationship between the number of components and the effects of multifaceted interventions. Only 29.4% of comparisons reported any economic data. Current guideline dissemination and implementation strategies can lead to improvements in care within the context of rigorous evaluative studies. However, there is an imperfect evidence base to support decisions about which guideline dissemination and implementation strategies are likely to be efficient under different circumstances. Decision makers need to use considerable judgment about how best to use the limited resources they have for quality improvement activities.


Breast cancer incidence after the introduction of mammography screening: what should be expected?
A prevalence peak is expected in breast cancer incidence when mammography screening begins, but afterward the incidence still may be elevated compared with prescreening levels. It is important to determine whether this is due to overdiagnosis (ie, the detection of asymptomatic disease that would otherwise not have arisen clinically). In the current study, the authors examined breast cancer incidence after the introduction of mammography screening in Denmark. Denmark has 2 regional screening programs targeting women ages 50 years to 69 years. The programs were initiated in 1991 and 1993, respectively. No screening takes place in the 13 other Danish regions. Data regarding incident breast cancers detected between 1979 and 2001 were retrieved from the Danish Cancer Registry for each screening region and for the rest of Denmark, and time trends in rates for women ages 50 years to 69 years were compared. From 1 program, individual screening data were used to analyze breast cancer incidence in women who were never screened, those who were screened for the first time, or those who previously were screened. The incidence of breast cancer was found to have increased regardless of screening. In the screening regions, a marked prevalence peak was observed, and the incidence hereafter was compatible with the level indicated by the 95% confidence limits for the regression curves for the rates in the prescreening period, taking into account the artificial ageing in the program, the influx of newcomers, and variations in the data. Women who had undergone previous screening were found to have the same incidence of breast cancer as women who were never screened. The data from the current study do not provide evidence of overdiagnosis of invasive breast cancer in the 2 Danish screening programs or, if overdiagnosis was found to occur, it was only of limited magnitude.


Trifecta Outcomes in Open, Laparoscopy or Robotic Partial Nephrectomy: Does the Surgical Approach Matter?
This retrospective study evaluated perioperative outcomes of open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN), and robot-assisted partial nephrectomy (RAPN) and identified predictive factors of Trifecta achievement for renal tumors that underwent partial nephrectomy (PN) in a single institutional cohort. The study involved patients who underwent PN from January 2011 to July 2018. Trifecta was defined as absence of perioperative complications, no positive surgical margins, and ischemia time <30 min. Fifty-five PN procedures were reviewed: 28 OPN, 14 LPN, and 13 RAPN. OPN, LPN and RAPN had similar median tumor size (5.75, 5.25, and 5 cm), nephrometry score (7, 6, and 6), and preoperative creatinine (1.09, 1.1, and 1.1 mg/dl, respectively). Blood loss was higher for OPN (550 ml) than for LPN (400 ml) and RAPN (300 ml), P = 0.042. Drain was removed after 6 days in OPN which was higher than LPN and RAPN (4.5 and 4 days, respectively), P = 0.008. OPN, LPN, and RAPN had similar median operative time (190, 180, and 180 min, respectively), P = 0.438. Median postoperative stay for OPN, LPN, and RAPN was 5, 6.5, and 10 days, respectively. Trifecta outcomes of 73.1%, 64.3%, and 61.53% were achieved in OPN, LPN, and RAPN, respectively, P = 0.730. It was concluded that Trifecta outcomes had no significant difference among OPN, LPN, and RAPN. LPN can produce as good results as RAPN. Keeping in mind the cost-effectiveness, LPN holds an important position in developing countries where expenditure by patient is a major factor.


Antibody Specificity Following a Recent Bordetella pertussis Infection in Adolescence Is Correlated With the Pertussis Vaccine Received in Childhood.
Bordetella (B.) pertussis resurgence affects not only the unvaccinated, but also the vaccinated population. Different vaccines are available, however, it is currently unknown whether the type of childhood vaccination has an influence on antibody responses following a B. pertussis infection later in life. Therefore, the study aim was to profile serum antibody responses in young adults with suspected B. pertussis infections, immunized during childhood with either whole-cell (wPV) or monocomponent acellular pertussis (aPV) vaccines. Serum anti-pertussis toxin (PTx) IgG antibody levels served as an indicator for a recent B. pertussis infection. Leftover sera from a diagnostic laboratory from 36 Danish individuals were included and divided into four groups based on immunization background (aPV vs. wPV) and serum anti-PTx IgG levels (- vs. +). Pertussis-specific IgG/IgA antibody levels and antigen specificity were determined by using multiplex immunoassays (MIA), one- and two-dimensional immunoblotting (1 & 2DEWB), and mass spectrometry. Besides enhanced anti-PTx levels, wPV(+) and aPV(+) groups showed increased IgG and IgA levels against pertactin, filamentous hemagglutinin, fimbriae 2/3, and pertussis outer membrane vesicles (OMV). In the wPV(-) and aPV(-) groups, only low levels of anti-OMV antibodies were detected. 1DEWB demonstrated that antibody patterns differed between groups but also between individuals with the same immunization background and anti-PTx levels. 2DWB analysis for serum IgG revealed 133 immunogenic antigens of which 40 were significantly different between groups allowing to differentiate wPV(+) and aPV(+) groups. Similarly, for serum IgA, 7 of 47 immunogenic protein spots were significantly different. This study demonstrated that B. pertussis infection-induced antibody responses were distinct on antigen level between individuals with either wPV or aPV immunization background. Importantly, only 2DEWB and not MIA could detect these differences indicating the potential of this method. Moreover, in individuals immunized with an aPV containing only PTx in childhood, the infection-induced antibody responses were not limited to PTx alone.


Western-style diets induce oxidative stress and dysregulate immune responses in the colon in a mouse model of sporadic colon cancer.
A Western-style diet (WD), defined by high-fat, low-calcium, and vitamin D content, is associated with increased risk of human colorectal cancer. Understanding molecular mechanisms altered by the WD is crucial to develop preventive and therapeutic strategies. Effects of a WD on the colonic transcriptome of C57Bl/6J mice, a model for sporadic colon cancer, were studied at endpoints before tumors occur. To assess whether a WD induces inflammatory changes, expression profiles of a broad spectrum of inflammatory proteins were performed and numbers of lamina propria macrophages were determined with semiquantitative morphometry. Transcriptome changes were translated into molecular interaction network maps and pathways. Pathways related to oxidative stress response; lipid, glutathione, and xenobiotic metabolism; and the immune response were perturbed by the WD. Several nuclear factor-erythroid 2-related factor 2- and aryl hydrocarbon receptor-dependent genes, including those coding for enzymes involved in phase 1 and 2 drug metabolism and oxidative stress responses, were induced. Oxidative stress was demonstrated by measurements of endogenous colonic redox-sensitive compound concentrations. Perturbations in immune response-related pathways, expression of inflammatory proteins, and increased numbers of lamina propria macrophages showed that the WD significantly alters the local colonic immune response. Collectively, these data suggest that consumption of a WD interferes with networks of related biological response pathways involving colonic lipid metabolism, oxidative stress, and the immune response. These new findings impact our understanding of links between consumption of WD and colon carcinogenesis, providing additional information for developing preventive means for decreasing colorectal cancer risk.


Why ritualized behavior? Precaution Systems and action parsing in developmental, pathological and cultural rituals.
Ritualized behavior, intuitively recognizable by its stereotypy, rigidity, repetition, and apparent lack of rational motivation, is found in a variety of life conditions, customs, and everyday practices: in cultural rituals, whether religious or non-religious; in many children's complicated routines; in the pathology of obsessive-compulsive disorders (OCD); in normal adults around certain stages of the life-cycle, birthing in particular. Combining evidence from evolutionary anthropology, neuropsychology and neuroimaging, we propose an explanation of ritualized behavior in terms of an evolved Precaution System geared to the detection of and reaction to inferred threats to fitness. This system, distinct from fear-systems geared to respond to manifest danger, includes a repertoire of clues for potential danger as well as a repertoire of species-typical precautions. In OCD pathology, this system does not supply a negative feedback to the appraisal of potential threats, resulting in doubts about the proper performance of precautions, and repetition of action. Also, anxiety levels focus the attention on low-level gestural units of behavior rather than on the goal-related higher-level units normally used in parsing the action-flow. Normally automatized actions are submitted to cognitive control. This "swamps" working memory, an effect of which is a temporary relief from intrusions but also their long-term strengthening. Normal activation of this Precaution System explains intrusions and ritual behaviors in normal adults. Gradual calibration of the system occurs through childhood rituals. Cultural mimicry of this system's normal input makes cultural rituals attention-grabbing and compelling. A number of empirical predictions follow from this synthetic model.


Acquisition and visualization techniques for narrow spectral color imaging.
This paper introduces a new approach in narrow-band imaging (NBI). Existing NBI techniques generate images by selecting discrete bands over the full visible spectrum or an even wider spectral range. In contrast, here we perform the sampling with filters covering a tight spectral window. This image acquisition method, named narrow spectral imaging, can be particularly useful when optical information is only available within a narrow spectral window, such as in the case of deep-water transmittance, which constitutes the principal motivation of this work. In this study we demonstrate the potential of the proposed photographic technique on nonunderwater scenes recorded under controlled conditions. To this end three multilayer narrow bandpass filters were employed, which transmit at 440, 456, and 470 nm bluish wavelengths, respectively. Since the differences among the images captured in such a narrow spectral window can be extremely small, both image acquisition and visualization require a novel approach. First, high-bit-depth images were acquired with multilayer narrow-band filters either placed in front of the illumination or mounted on the camera lens. Second, a color-mapping method is proposed, using which the input data can be transformed onto the entire display color gamut with a continuous and perceptually nearly uniform mapping, while ensuring optimally high information content for human perception.


A numerical classification of the genus Bacillus.
Three hundred and sixty-eight strains of aerobic, endospore-forming bacteria which included type and reference cultures of Bacillus and environmental isolates were studied. Overall similarities of these strains for 118 unit characters were determined by the SSM, SJ and DP coefficients and clustering achieved using the UPGMA algorithm. Test error was within acceptable limits. Six cluster-groups were defined at 70% SSM, which corresponded to 69% SP and 48-57% SJ. Groupings obtained with the three coefficients were generally similar but there were some changes in the definition and membership of cluster-groups and clusters, particularly with the SJ coefficient. The Bacillus strains were distributed among 31 major (4 or more strains), 18 minor (2 or 3 strains) and 30 single-member clusters at the 83% SSM level. Most of these clusters can be regarded as taxospecies. The heterogeneity of several species, including Bacillus brevis, B. circulans, B. coagulans, B. megateriun, B. sphaericus and B. stearothermophilus, has been indicated and the species status of several taxa of hitherto uncertain validity confirmed. Thus on the basis of the numerical phenetic and appropriate (published) molecular genetic data, it is proposed that the following names be recognized; Bacillus flexus (Batchelor) nom. rev., Bacillus fusiformis (Smith et al.) comb. nov., Bacillus kaustophilus (Prickett) nom. rev., Bacillus psychrosaccharolyticus (Larkin & Stokes) nom. rev. and Bacillus simplex (Gottheil) nom. rev. Other phenetically well-defined taxospecies included 'B. aneurinolyticus', 'B. apiarius', 'B. cascainensis', 'B. thiaminolyticus' and three clusters of environmental isolates related to B. firmus and previously described as 'B. firmus-B. lentus intermediates'. Future developments in the light of the numerical phenetic data are discussed.


Designing and evaluating health systems level hypertension control interventions for African-Americans: lessons from a pooled analysis of three cluster randomized trials.
African-Americans (AAs) have a high prevalence of hypertension and their blood pressure (BP) control on treatment still lags behind other groups. In 2004, NHLBI funded five projects that aimed to evaluate clinically feasible interventions to effect changes in medical care delivery leading to an increased proportion of AA patients with controlled BP. Three of the groups performed a pooled analysis of trial results to determine: 1) the magnitude of the combined intervention effect; and 2) how the pooled results could inform the methodology for future health-system level BP interventions. Using a cluster randomized design, the trials enrolled AAs with uncontrolled hypertension to test interventions targeting a combination of patient and clinician behaviors. The 12-month Systolic BP (SBP) and Diastolic BP (DBP) effects of intervention or control cluster assignment were assessed using mixed effects longitudinal regression modeling. 2,015 patients representing 352 clusters participated across the three trials. Pooled BP slopes followed a quadratic pattern, with an initial decline, followed by a rise toward baseline, and did not differ significantly between intervention and control clusters: SBP linear coefficient = -2.60±0.21 mmHg per month, p<0.001; quadratic coefficient = 0.167± 0.02 mmHg/month, p<0.001; group by time interaction group by time group x linear time coefficient=0.145 ± 0.293, p=0.622; group x quadratic time coefficient= -0.017 ± 0.026, p=0.525). RESULTS were similar for DBP. The individual sites did not have significant intervention effects when analyzed separately. Investigators planning behavioral trials to improve BP control in health systems serving AAs should plan for small effect sizes and employ a "run-in" period in which BP can be expected to improve in both experimental and control clusters.


The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.
Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments. To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Diffuse, nonlength-dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, nonlength-dependent neuropathies are Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyotrophy (radiculoplexus neuropathy) is lacking. Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the diagnostic evaluation and provide information on the localization and pathophysiology of nerve injury.