Replication Validity of Initial Association Studies: A Comparison between Psychiatry, Neurology and Four Somatic Diseases.
There are growing concerns about effect size inflation and replication validity of association studies, but few observational investigations have explored the extent of these problems. Using meta-analyses to measure the reliability of initial studies and explore whether this varies across biomedical domains and study types (cognitive/behavioral, brain imaging, genetic and "others"). We analyzed 663 meta-analyses describing associations between markers or risk factors and 12 pathologies within three biomedical domains (psychiatry, neurology and four somatic diseases). We collected the effect size, sample size, publication year and Impact Factor of initial studies, largest studies (i.e., with the largest sample size) and the corresponding meta-analyses. Initial studies were considered as replicated if they were in nominal agreement with meta-analyses and if their effect size inflation was below 100%. Nominal agreement between initial studies and meta-analyses regarding the presence of a significant effect was not better than chance in psychiatry, whereas it was somewhat better in neurology and somatic diseases. Whereas effect sizes reported by largest studies and meta-analyses were similar, most of those reported by initial studies were inflated. Among the 256 initial studies reporting a significant effect (p<0.05) and paired with significant meta-analyses, 97 effect sizes were inflated by more than 100%. Nominal agreement and effect size inflation varied with the biomedical domain and study type. Indeed, the replication rate of initial studies reporting a significant effect ranged from 6.3% for genetic studies in psychiatry to 86.4% for cognitive/behavioral studies. Comparison between eight subgroups shows that replication rate decreases with sample size and "true" effect size. We observed no evidence of association between replication rate and publication year or Impact Factor. The differences in reliability between biological psychiatry, neurology and somatic diseases suggest that there is room for improvement, at least in some subdomains.


Risk factors contributing to gingival recession among patients undergoing different orthodontic treatment modalities.
The aim of this study was to investigate the risk factors contributing to gingival recession among patients undergoing orthodontic treatment. Records of 100 Caucasian patients who completed orthodontic treatment were evaluated before and after treatment. Intercanine and molar widths, arch perimeter, arch depth, and keratinized gingival height were measured for both arches. The association of orthodontic treatment strategy (changing incisal inclination, expansion, and extraction), keratinized gingival height, and various other measurements with gingival recession was evaluated by using generalized linear mixed models with logistic regression analysis. For each 1 mm increase in pre- and post-treatment keratinized gingival height, there was 0.77 and 0.51 times lower odds of gingival recession. For each 1 mm increase in post-treatment intercanine width, there was 0.80 times lower odds of gingival recession. And for each 1 mm increase in change in the arch depth, there was 1.16 times higher odds of gingival recession. For each 1 mm increase in pre- and post-treatment mandibular symphysis width, there was 0.47 and 0.39 times lower odds of gingival recession. Regardless of the type of orthodontic treatment, increased keratinized gingival height, mandibular symphysis width, and post-treatment intercanine width lower the risk of gingival recession.


Pancreatic acinar cell carcinoma is associated with BRCA2 germline mutations: a case report and literature review.
Acinar cell carcinoma (ACC) is a rare pancreatic neoplasm with dismal prognosis. Insights into the molecular basis of ACC can pave the way for the application of more effective, personalized therapies and detection of patients with hereditary predisposition. Molecular analysis revealed a germline BRCA2 (and CHEK2) mutation in a patient with a rare pancreatic ACC with extensive intraductal growth. Somatic loss of the wild-type BRCA2 allele in the tumor indicated the causal relationship of ACC with the germline defect. A thorough literature review identified another nine ACCs associated with germline BRCA2 mutation and two ACCs associated with germline BRCA1 mutation, resulting in a prevalence of BRCA1/2 germline mutations in almost 7% of ACCs. Moreover, somatic BRCA1/2 alterations are reported in 16% of sporadic ACCs. Overall, about one fifth (22%) of all pancreatic ACCs exhibit BRCA1/2 deficiency. This study underscores the important role of BRCA1/2 mutations in pancreatic ACC. All ACC patients should undergo genetic testing for BRCA1/2 mutations to identify carriers of pathogenic variants. This will allow to select patients that can benefit from targeted therapies directed against BRCA1/2-deficient tumors and is also crucial as a referral to genetic screening for the relatives of affected individuals carrying germline BRCA1/2 alterations. Abbreviations: ACC: acinar cell carcinoma; HBOC: Hereditary Breast and Ovarian Cancer; LOH: loss of heterozygosity; PARP: poly (ADP-ribose) polymerase; PDAC: pancreatic ductal adenocarcinoma; PP: pancreatic panniculitis; SD: standard deviation; WES: whole-exome sequencing.


A standardized and reproducible urine preparation protocol for cancer biomarkers discovery.
A suitable and standardized protein purification technique is essential to maintain consistency and to allow data comparison between proteomic studies for urine biomarker discovery. Ultimately, efforts should be made to standardize urine preparation protocols. The aim of this study was to develop an optimal analytical protocol to achieve maximal protein yield and to ensure that this method was applicable to examine urine protein patterns that distinguish disease and disease-free states. In this pilot study, we compared seven different urine sample preparation methods to remove salts, and to precipitate and isolate urinary proteins. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) profiles showed that the sequential preparation of urinary proteins by combining acetone and trichloroacetic acid (TCA) alongside high speed centrifugation (HSC) provided the best separation, and retained the most urinary proteins. Therefore, this approach is the preferred method for all further urine protein analysis.


Regulatory mechanisms involved in the control of ubiquitin homeostasis.
Ubiquitin (Ub) modification plays an essential role in the regulation of various cellular processes. Ub performs a remarkable array of cellular tasks through the production of a large number of ubiquitinated proteins; such tasks require many Ubs. Ubs are expressed abundantly from several Ub encoding genes, though not in excess. Rather, Ub expression is tightly regulated through various control mechanisms. Recent studies have shown that the cellular Ub level is regulated by balanced activities of deubiquitinating enzymes and their regulators. Here, we review the current understandings of the regulatory mechanisms that control Ub expression and its metabolism and maintain Ub homeostasis.


A simple sign for recognizing off-axis OCT measurement beam placement in the context of multicentre studies.
Optical coherence tomography (OCT) allows quantification of the thickness of the retinal nerve fibre layer (RNFL) thickness, a potential biomarker for neurodegeneration. The estimated annual RNFL loss in multiple sclerosis amounts to 2 μm using time domain OCT. The recognition of measurement artifacts exceeding this limit is relevant for the successful use of OCT as a secondary outcome measure in clinical trials. Prospective study design. An exploratory pilot study (ring and volume scans) followed by a cohort study (1,980 OCT ring scans). The OCT measurement beam was placed off-axis to the left, right, top and bottom of the subjects pupil and RNFL thickness of these scans were compared to the centrally placed reference scans. Off-axis placement of the OCT measurement beam resulted in significant artifacts in RNFL thickness measurements (95%CI 9μm, maximal size of error 42μm). Off-axis placement gave characteristic patterns of the OCT live images which are not necessarily saved for review. Off-axis placement also causes regional inhomogeneity of reflectivity in the outer nuclear (ONL) and outer plexiform layers (OPL) which remains visible on scans saved for review. Off-axis beam placement introduces measurement artifacts at a magnitude which may mask recognition of RNFL loss due to neurodegeneration in multiple sclerosis. The resulting pattern in the OCT live image can only be recognised by the technician capturing the scans. Once the averaged scans have been aligned this pattern is lost. Retrospective identification of this artifact is however possible by presence of regional inhomogeneity of ONL/OPL reflectivity. This simple and robust sign may be considered for quality control criteria in the setting of multicentre OCT studies. The practical advice of this study is to keep the OCT image in the acquisition window horizontally aligned whenever possible.


Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its α-Helical Conformation, and Inhibits γ-Secretase Nonselectively in Liposomes.
Bexarotene is a pleiotropic molecule that has been proposed as an amyloid-β (Aβ)-lowering drug for the treatment of Alzheimer's disease (AD). It acts by upregulation of an apolipoprotein E (apoE)-mediated Aβ clearance mechanism. However, whether bexarotene induces removal of Aβ plaques in mouse models of AD has been controversial. Here, we show by NMR and CD spectroscopy that bexarotene directly interacts with and stabilizes the transmembrane domain α-helix of the amyloid precursor protein (APP) in a region where cholesterol binds. This effect is not mediated by changes in membrane lipid packing, as bexarotene does not share with cholesterol the property of inducing phospholipid condensation. Bexarotene inhibited the intramembrane cleavage by γ-secretase of the APP C-terminal fragment C99 to release Aβ in cell-free assays of the reconstituted enzyme in liposomes, but not in cells, and only at very high micromolar concentrations. Surprisingly, in vitro, bexarotene also inhibited the cleavage of Notch1, another major γ-secretase substrate, demonstrating that its inhibition of γ-secretase is not substrate specific and not mediated by acting via the cholesterol binding site of C99. Our data suggest that bexarotene is a pleiotropic molecule that interfere with Aβ metabolism through multiple mechanisms.


Behavior of metallic silver nanoparticles in a pilot wastewater treatment plant.
We investigated the behavior of metallic silver nanoparticles (Ag-NP) in a pilot wastewater treatment plant (WWTP) fed with municipal wastewater. The treatment plant consisted of a nonaerated and an aerated tank and a secondary clarifier. The average hydraulic retention time including the secondary clarifier was 1 day and the sludge age was 14 days. Ag-NP were spiked into the nonaerated tank and samples were collected from the aerated tank and from the effluent. Ag concentrations determined by inductively coupled plasma-mass spectrometry (ICP-MS) were in good agreement with predictions based on mass balance considerations. Transmission electron microscopy (TEM) analyses confirmed that nanoscale Ag particles were sorbed to wastewater biosolids, both in the sludge and in the effluent. Freely dispersed nanoscale Ag particles were only observed in the effluent during the initial pulse spike. X-ray absorption spectroscopy (XAS) measurements indicated that most Ag in the sludge and in the effluent was present as Ag(2)S. Results from batch experiments suggested that Ag-NP transformation to Ag(2)S occured in the nonaerated tank within less than 2 h. Physical and chemical transformations of Ag-NP in WWTPs control the fate, the transport and also the toxicity and the bioavailability of Ag-NP and therefore must be considered in future risk assessments.


A neural basis of probabilistic computation in visual cortex.
Bayesian models of behavior suggest that organisms represent uncertainty associated with sensory variables. However, the neural code of uncertainty remains elusive. A central hypothesis is that uncertainty is encoded in the population activity of cortical neurons in the form of likelihood functions. We tested this hypothesis by simultaneously recording population activity from primate visual cortex during a visual categorization task in which trial-to-trial uncertainty about stimulus orientation was relevant for the decision. We decoded the likelihood function from the trial-to-trial population activity and found that it predicted decisions better than a point estimate of orientation. This remained true when we conditioned on the true orientation, suggesting that internal fluctuations in neural activity drive behaviorally meaningful variations in the likelihood function. Our results establish the role of population-encoded likelihood functions in mediating behavior and provide a neural underpinning for Bayesian models of perception.


Activation of TRPV1 in nucleus tractus solitarius reduces brown adipose tissue thermogenesis, arterial pressure, and heart rate.
The sympathetic nerve activity (SNA) to brown adipose tissue (BAT) regulates BAT thermogenesis to defend body temperature in cold environments or to produce fever during immune responses. The vagus nerve contains afferents that inhibit the BAT SNA and BAT thermogenesis evoked by skin cooling. We sought to determine whether activation of transient receptor potential vanilloid 1 (TRPV1) channels in the nucleus tractus solitarius (NTS), which are prominently expressed in unmyelinated vagal afferents, would affect cold-evoked BAT thermogenesis, cardiovascular parameters, or their vagal afferent-evoked responses. In urethane-chloralose-anesthetized rats, during skin cooling, nanoinjection of the TRPV1-agonist resiniferatoxin in NTS decreased BAT SNA (from 695 ± 195% of baseline during cooling to 103 ± 8% of baseline after resiniferatoxin), BAT temperature (-0.8 ± 0.1°C), expired CO2 (-0.3 ± 0.04%), mean arterial pressure (MAP; -20 ± 5 mmHg), and heart rate (-44 ± 11 beats/min). Pretreatment of NTS with the TRPV1 antagonist capsazepine prevented these resiniferatoxin-mediated effects. Intravenous injection of the TRPV1 agonist dihydrocapsaicin also decreased all the measured variables (except MAP). Bilateral cervical or subdiaphragmatic vagotomy attenuated the decreases in BAT SNA and thermogenesis evoked by nanoinjection of resiniferatoxin in NTS but did not prevent the decreases in BAT SNA and BAT thermogenesis evoked by intravenous dihydrocapsaicin. We conclude that activation of TRPV1 channels in the NTS of vagus nerve intact rats inhibits BAT SNA and decreases BAT metabolism, blood pressure, and heart rate. In contrast, the inhibition of BAT thermogenesis following systemic administration of dihydrocapsaicin does not require vagal afferent activity, consistent with a nonvagal pathway through which systemic TRPV1 agonists can inhibit BAT thermogenesis.


Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer.
Reactivation of telomerase, the chromosome end-replicating enzyme, drives human cell immortality and cancer. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter occur at high frequency in multiple cancers, including urothelial cancer (UC), but their effect on telomerase function has been unclear. In a study of 23 human UC cell lines, we show that these promoter mutations correlate with higher levels of TERT messenger RNA (mRNA), TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and UC patient outcome, we find that elevated TERT mRNA expression strongly correlates with reduced disease-specific survival in two independent UC patient cohorts (n = 35; n = 87). These results suggest that high telomerase activity may be a better marker of aggressive UC tumors than TERT promoter mutations alone.


Successful treatment of melanoma metastatic to the left atrium using external beam radiation therapy.
The successful treatment of a patient with primary nasal melanoma metastatic to the lung, pulmonary vein, and left atrium using radiation therapy is described. The patient was effectively treated with a conventional external beam radiation fractionation scheme (rather than a more commonly used hypofractioned regimen) that was utilized to minimize risk of arterial embolus of the tumor or rupture of a vessel wall. A post-treatment CT demonstrated a significant decrease in the caliber of the right pulmonary vein and tumor thrombus. The patient never developed cardiac valvular dysfunction or acute life-threatening massive embolism of tumor from the atrium. Unfortunately, the patient experienced clinical decline secondary to the massive progression of intra-abdominal disease and subsequently died from multiple liver metastases and liver failure. Numerous studies and this case report demonstrate that radiation therapy can be very effective in the treatment of malignant melanoma, especially when only small volumes of disease need to be treated and adequate total doses are used. Therefore, radiation therapy appears to play an important yet underutilized role in the treatment of metastatic melanomas.


Inhibition of aldosterone production by an atrial extract.
Crude extracts of rat atria reduced the basal amount of aldosterone released from rat zona glomerulosa cells and partially inhibited aldosterone stimulation by adrenocorticotropic hormone and angiotensin II. The destruction of this activity by trypsin suggests that the active factor is a peptide, possibly atrial natriuretic factor. These data suggest that atrial natriuretic factor affects sodium excretion by the kidneys both directly and through the inhibition of aldosterone production.


Molecular regulation of adipocyte differentiation.
Significant advances have been made recently toward understanding the molecular events that regulate adipocyte differentiation. In vitro models of adipogenesis, such as the 3T3-L1 and F-442A preadipocyte cell lines have proven to be an invaluable resource in elucidating mechanisms of adipocyte differentiation. Subject to modulation by hormonal, dietary, and genetic influences, the differentiation program now appears to be distinctly controlled through the coordinate regulation of transcription factors that predominantly include members of the C/EBP and PPAR families. Increased understanding of these critical factors and how they are regulated will provide insights into adipose tissue development as well as treatment of obesity.


Assessment of water, sanitation, and hygiene practices and associated factors in a Buruli ulcer endemic district in Benin (West Africa).
Control of neglected tropical diseases (NTDs) requires multiple strategic approaches including water, sanitation and hygiene services (WASH). Buruli ulcer (BU), one of the 17 NTDs, remains a public health issue in Benin particularly in the district of Lalo. The availability of water as well as good hygiene are important for the management of Buruli ulcer particularly in the area of wound care one of the main component of the treatment of BU lesions. Given the growing importance of WASH in controlling NTDs and in order to assess the baseline for future cross-cutting interventions, we report here on the first study evaluating the level of WASH and associated factors in Lalo, one of the most BU-endemic districts in Benin. A cross-sectional study was carried to assess WASH practices and associated factors in the district of Lalo. Data were collected from 600 heads of household using structured pretested questionnaire and observations triangulated with qualitative information obtained from in-depth interviews of patients, care-givers and community members. Univariate and multivariate analysis were carried to determine the relationships between the potential associated factors and the sanitation as well as hygiene status. BU is an important conditions in the district of Lalo with 917 new cases detected from 2006 to 2012. More than 49 % of the household surveyed used unimproved water sources for their daily needs. Only 8.7 % of the investigated household had improved sanitation facilities at home and 9.7 % had improved hygiene behavior. The type of housing as an indicator of the socioeconomic status, the permanent availability of soap and improved hygiene practices were identified as the main factors positively associated with improved sanitation status. In the district of Lalo in Benin, one of the most endemic for BU, the WASH indicators are very low. This study provides baseline informations for future cross-cutting interventions in this district.


Residential aged care: the last frontier for palliative care.
This paper is a report of an explorative study describing the perceptions and beliefs about palliative care among nurses and care assistants working in residential aged care facilities in Australia. Internationally, the number of people dying in residential aged care facilities is growing. In Australia, aged care providers are being encouraged and supported by a positive policy platform to deliver a palliative approach to care, which has generated significant interest from clinicians, academics and researchers. However, a little is known about the ability and capacity of residential aged care services to adopt and provide a palliative approach to care. Focus groups were used to investigate the collective perceptions and beliefs about palliative care in a convenience sample of nurses and care assistants working in residential aged care facilities in Australia. Thematic content analysis was used to analyse the data, which were collected during 2004. Four major themes emerged: (1) being like family; (2) advocacy as a key role; (3) challenges in communicating with other healthcare providers; (4) battling and striving to succeed against the odds. Although participants described involvement and commitment to quality palliative care, they also expressed a need for additional education and support about symptom control, language and access to specialist services and resources. The residential aged care sector is in need of support for providing palliative care, yet there are significant professional and system barriers to care delivery. The provision of enhanced palliative care educational and networking opportunities for nurses and care assistants in residential aged care, augmented by a supportive organizational culture, would assist in the adoption of a palliative approach to service delivery and requires systematic investigation.


Landscape-scale variation in plant community composition of an African savanna from airborne species mapping.
Information on landscape-scale patterns in species distributions and community types is vital for ecological science and effective conservation assessment and planning. However, detailed maps of plant community structure at landscape scales seldom exist due to the inability of field-based inventories to map a sufficient number of individuals over large areas. The Carnegie Airborne Observatory (CAO) collected hyperspectral and lidar data over Kruger National Park, South Africa, and these data were used to remotely identify > 500 000 tree and shrub crowns over a 144-km2 landscape using stacked support vector machines. Maps of community compositional variation were produced by ordination and clustering, and the importance of hillslope-scale topo-edaphic variation in shaping community structure was evaluated with redundancy analysis. This remote species identification approach revealed spatially complex patterns in woody plant communities throughout the landscape that could not be directly observed using field-based methods alone. We estimated that topo-edaphic variables representing catenal sequences explained 21% of species compositional variation, while we also uncovered important community patterns that were unrelated to catenas, indicating a large role for other soil-related factors in shaping the savanna community. Our results demonstrate the ability of airborne species identification techniques to map biodiversity for the evaluation of ecological controls on community composition over large landscapes.


High-Sensitivity Cardiac Troponin I as a Gatekeeper for Coronary Computed Tomography Angiography and Stress Testing in Patients with Acute Chest Pain.
Most patients presenting to the emergency department (ED) with suspected acute coronary syndrome (ACS) undergo noninvasive cardiac testing with a low diagnostic yield. We determined whether a combination of high-sensitivity cardiac troponin I (hs-cTnI) and cardiovascular risk factors might improve selection of patients for cardiac testing. We included patients from the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) I and II trials who presented to the ED with acute chest pain and were referred for cardiac testing. Based on serial hs-cTnI measurements and cardiovascular risk factors, we derived and validated the criterion for no need of cardiac testing. We predicted the effect of this criterion on the effectiveness of patient management. A combination of baseline hs-cTnI (<4 ng/L) and cardiovascular risk factors (<2) ruled out ACS with a negative predictive value of 100% in ROMICAT I. We validated this criterion in ROMICAT II, identifying 29% patients as not needing cardiac testing. An additional 5% of patients were identified by adding no change or a decrease between baseline and 2 h hs-cTnI as a criterion. Assuming those patients would be discharged from the ED without cardiac testing, implementation of hs-cTnI would increase ED discharge rate (24.3% to 50.2%, P < 0.001) and decrease the length of hospital stay (21.4 to 8.2 h, P < 0.001), radiation dose (10.2 to 7.7 mSv, P < 0.001), and costs of care (4066 to 3342 US$, P < 0.001). We derived and validated a criterion for combined hs-cTnI and cardiovascular risk factors that identified acute chest pain patients with no need for cardiac testing and could improve effectiveness of patient management. ClinicalTrials.gov Identifiers: NCT00990262 and NCT01084239.


Pharmacokinetics and pharmacodynamics of diclofenac in the presence and absence of glibenclamide in the rat.
There are evidences that glibenclamide, a sulfonylurea antidiabetic agent, reduces the analgesic action of non-steroidal antiinflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. The purpose of this work was to examine in the rat if such interaction involves pharmacokinetic mechanisms or is solely limited to the pharmacodynamic level. All studies were carried out in female Wistar rats. Analgesia was assessed using the formalin test. Fifty microliters of diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection and a reduction in formalin-induced flinching was interpreted as an analgesic response. Rats were treated with oral diclofenac (3-18 mg/kg) in presence and the absence of oral glibenclamide (1-30 mg/kg). To evaluate the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (18 mg/kg) was studied in presence and the absence of glibenclamide (10 mg/kg). Oral administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Coadministration of glibenclamide significantly reduced diclofenac-induced antinociception. Notwithstanding, the interaction does no appear to involve pharmacokinetic mechanisms, as oral glibenclamide failed to produce any significant alteration in oral diclofenac bioavailability. Concomitant systemic administration of glibenclamide and diclofenac results in a reduction of the analgesic effect of the NSAID in the formalin test in the rat. This interaction, however, appears due solely to a pharmacodynamic mechanisms as diclofenac pharmacokinetics are not altered.


STUDIES IN EDEMA : VI. THE INFLUENCE OF ADRENALIN ON ABSORPTION FROM THE PERITONEAL CAVITY, WITH SOME REMARKS ON THE INFLUENCE OF CALCIUM CHLORIDE ON ABSORPTION.
1. Adrenalin injected intraperitoneally increases the rapidity of absorption of fluid from the peritoneal cavity, independently of whether the solution to be absorbed is hypotonic or hypertonic or is approximately isotonic with the blood serum. The intravenous injection of adrenalin also increases the absorption of fluid, but not so markedly as does the intraperitoneal injection. 2. Adrenalin injected either intraperitoneally or intravenously increases the quantity of sodium chloride absorbed. The relative absorption of sodium chloride-the movement from the peritoneal cavity of sodium chloride, as compared with the movement of water-is slightly increased when 0.85 per cent. of sodium chloride solution and adrenalin are injected intraperitoneally; but it is diminished when adrenalin is injected intravenously, or when 1.5 per cent. sodium chloride solution and adrenalin are injected. When distilled water has been injected intraperitoneally, adrenalin decreases the relative amount of sodium chloride in the peritoneal fluid-a fact that is evidently related to the increased elimination of sodium chloride through the kidneys under the influence of adrenalin. 3. When 0.85 per cent. sodium chloride solution is injected into the peritoneal cavity, the blood becomes diluted after two hours and a half. When adrenalin is also injected, the dilution of the blood is less marked, in spite of the increased absorption under the influence of adrenalin. When distilled water is injected into the peritoneal cavity, the blood is diluted equally in control and adrenalin experiments. When 1.5 per cent. sodium chloride solution is injected, the dilution of the blood is very slight, and in adrenalin experiments it is the same as in control experiments or very slightly greater than in control experiments. 4. The increase of absorption from the peritoneal cavity caused by the injection of adrenalin is not due to the increased diuresis caused by the injection of this substance. 5. The injection of adrenalin causes a temporary increase in the osmotic pressure of the blood, which gradually returns to normal. Under certain conditions, after the injection of adrenalin, there is a tendency toward maintaining the higher osmotic pressure of the blood serum, even up to the end of the experiment. We have reason to believe that this increase in the osmotic pressure of the blood is the main factor in increasing the absorption of fluid from the peritoneal cavity. 6. In experiments in which 0.85 per cent. sodium chloride solution has been injected intraperitoneally, either with or without adrenalin, there exists a tendency of the peritoneal fluid to attain a greater osmotic pressure than the blood serum, in spite of the fact that the injected fluid is slightly hypotonic as compared with the blood serum. We note a similar condition in cases of general edema in man, in which the osmotic pressure of the ascitic fluid is greater than that of the other edematous fluids, or even that of the blood serum. There exists, therefore, a mechanism that causes the passage of osmotically active substances from the blood or from the tissues into the peritoneal cavity, and that causes the osmotic pressure of the peritoneal fluid to become higher than that of the blood. It follows from our experiments that this mechanism, which causes the ascites in edematous persons to have such a high osmotic pressure, is not dependent upon certain pathological changes in the lining membranes or upon other pathological conditions, but exists already in normal animals. 7. The addition of 1.22 per cent. calcium chloride solution to 0.83 per cent. sodium chloride solution, in such proportions as we used in our infusion experiments, in which we determined the transudation into the peritoneal cavity, delays the absorption of fluid from the peritoneal cavity but very slightly. Therefore, calcium chloride increases directly the transudation into the peritoneal cavity and does not cause an increase in the amount of fluid in the peritoneal cavity merely by inhibiting the absorption. 8. It follows that adrenalin does not increase the amount of peritoneal transudate found after the intravenous infusion of large quantities of sodium chloride solution, to which adrenalin has been added, by delaying the absorption from the peritoneal cavity. The increased amounts of peritoneal fluid must be due to increased transudation into the peritoneal cavity; and the adrenalin, in view of its marked effect on absorption from the peritoneal cavity, must increase the movement of fluid into the peritoneal cavity much more strongly than could be assumed from the figures obtained in the infusion experiments.


Photonic band structures of periodic arrays of pores in a metallic host: tight-binding beyond the quasistatic approximation.
We have calculated the photonic band structures of metallic inverse opals and of periodic linear chains of spherical pores in a metallic host, below a plasma frequency ωp. In both cases, we use a tight-binding approximation, assuming a Drude dielectric function for the metallic component, but without making the quasistatic approximation. The tight-binding modes are linear combinations of the single-cavity transverse magnetic (TM) modes. For the inverse-opal structures, the lowest modes are analogous to those constructed from the three degenerate atomic p-states in fcc crystals. For the linear chains, in the limit of small spheres compared to a wavelength, the results bear some qualitative resemblance to the dispersion relation for metal spheres in an insulating host, as calculated by Brongersma et al. [Phys. Rev. B 62, R16356 (2000)]. Because the electromagnetic fields of these modes decay exponentially in the metal, there are no radiative losses, in contrast to the case of arrays of metallic spheres in air. We suggest that this tight-binding approach to photonic band structures of such metallic inverse materials may be a useful approach for studying photonic crystals containing metallic components, even beyond the quasistatic approximation.


Improved electrochemical performance of nitrogen doped TiO2-B nanowires as anode materials for Li-ion batteries.
N-doped TiO2-B nanowires are prepared by the solvothermal method using TiN nanoparticles as the starting material. X-ray photoelectron spectroscopy shows that the N dopants preferentially occupy the interstitial sites of TiO2-B up to a content of ∼0.55 at%. Above this critical value, the N dopants will substitute the oxygen atoms which improve the electronic conductivity of TiO2-B. The maximum proportion of substituted-N in the TiO2-B nanowires is ∼1.3 at%. Raman scattering shows that the substituted-N strengthens the Ti(1)-O1-Ti(2) and O1-Ti(1)-O3 bonds of TiO2-B. This improves the stability of the corresponding local structures, thus reducing the distortion of the Li(+) diffusion channel along the b-axis of TiO2-B. As a result, the substituted-N has more of an impact on the electrochemical properties of TiO2-B than the interstitial-N does. The TiO2-B nanowires containing substituted-N dopants exhibit a remarkably enhanced electrochemical performance compared to pure TiO2-B. They show a discharge capacity of 153 mA h g(-1) at the 20 C rate with a capacity retention of 76% after 1000 cycles. In addition, they can deliver a discharge capacity of 100 mA h g(-1) at an ultra-high rate of 100 C, indicating their great potential in high power lithium ion batteries.


Ancient DNA evidence reveals that the Y chromosome haplogroup Q1a1 admixed into the Han Chinese 3,000 years ago.
Y chromosome haplogroup Q1a1 is found almost only in Han Chinese populations. However, it has not been found in ancient Han Chinese samples until now. Thus, the origin of haplogroup Q1a1 in Han Chinese is still obscure. This study attempts to provide answer to this question, and to uncover the origin and paternal genetic structure of the ancestors of the Han Chinese. Eighty-nine ancient human remains that were excavated from the presumed geographic source of the Han Chinese and dated to approximately 3,000 years ago were treated by the amelogenin gene polymerase chain reaction test, to determine their sex. Then, Y chromosome single nucleotide polymorphisms were subsequently analyzed from the samples detected as male. Samples from 27 individuals were successfully amplified. Their haplotypes could be attributed to haplogroups N, O*, O2a, O3a, and Q1a1. Analyses showed that the assigned haplogroup of each sample is correlated to the suspected social status and observed burial custom associated with the sample. The origins of the observed haplotypes and their distribution in present day Han Chinese and in the samples suggest that haplogroup Q1a1 was probably introduced into the Han Chinese population approximately 3,000 years ago.


Mobile phone use and risk of parotid gland tumor.
Handheld mobile phones were introduced in Denmark and Sweden during the late 1980s. This makes the Danish and Swedish populations suitable for a study aimed at testing the hypothesis that long-term mobile phone use increases the risk of parotid gland tumors. In this population-based case-control study, the authors identified all cases aged 20-69 years diagnosed with parotid gland tumor during 2000-2002 in Denmark and certain parts of Sweden. Controls were randomly selected from the study population base. Detailed information about mobile phone use was collected from 60 cases of malignant parotid gland tumors (85% response rate), 112 benign pleomorphic adenomas (88% response rate), and 681 controls (70% response rate). For regular mobile phone use, regardless of duration, the risk estimates for malignant and benign tumors were 0.7 (95% confidence interval: 0.4, 1.3) and 0.9 (95% confidence interval: 0.5, 1.5), respectively. Similar results were found for more than 10 years' duration of mobile phone use. The risk estimate did not increase, regardless of type of phone and amount of use. The authors conclude that the data do not support the hypothesis that mobile phone use is related to an increased risk of parotid gland tumors.


[Minimum quality threshold in preclinical sepsis studies (MQTiPSS): quality threshold for types of infections and organ dysfunction endpoints].
Although the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review has not been done for preclinical models. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling reviewed the 260 most highly cited papers between 2003 and 2012 using sepsis models to create a series of recommendations. This Part II report provides recommendations for the types of infections and documentation of organ injury in preclinical sepsis models. Concerning the types of infections, the review showed that the cecal ligation and puncture model was used for 44% of the studies while 40% injected endotoxin. Recommendation #8 (numbered sequentially from Part I): endotoxin injection should not be considered as a model of sepsis; live bacteria or fungal strains derived from clinical isolates are more appropriate. Recommendation #9: microorganisms should replicate those typically found in human sepsis. Sepsis-3 states that sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection, but the review of the papers showed limited attempts to document organ dysfunction. Recommendation #10: organ dysfunction definitions should be used in preclinical models. Recommendation #11: not all activities in an organ/system need to be abnormal to verify organ dysfunction. Recommendation #12: organ dysfunction should be measured in an objective manner using reproducible scoring systems. Recommendation #13: not all experiments must measure all parameters of organ dysfunction, but investigators should attempt to fully capture as much information as possible. These recommendations are proposed as "best practices" for animal models of sepsis.


[Platelet adhesion and adhesive proteins--how to measure the platelet adhesiveness].
We examined, platelet adhesive function in vivo by comparing the platelet retention rate (PRR) with other laboratory tests. In 71 patients, PRR did not correlate with bleeding time (BT), ristocetin-induced platelet agglutination (RIPA), vWF:AG, vWF:RCo, FVIII:C, fibrinogen, platelets counts or platelet aggregation tests. Among them, the coincidence rate of PRR with BT seems relatively better than that of other tests. In patients with Bernard-Soulier syndrome (BSS), PRR, RIPA and high shear-induced platelet aggregation (SIPA), measured using a cone-plate type instrument, were decreased, while platelet adhesion in a static system and SIPA at a low shear rate were normal. In patients with Glanzmann's thrombasthenia (TA), PRR and SIPA were decreased at both high and low shear rates, while RIPA and platelet adhesion were normal in a static system. In patients with deficient glycoprotein Ia/IIa complex which is one of the putative receptors for collagen, platelet adhesion in a static system is markedly decreased. In patients with von Willebrand disease, the pattern of platelet adhesion tests was similar to that of BSS patients, while in patients with afibrinogenemia, it was similar to that of TA patients except for SIPA at a high shear rate. The various experiments using monoclonal antibodies support these abnormalities. These findings, suggest that PRR is a suitable screening test, but further rapid and easy tests will be necessary to diagnose the defects of platelet adhesion at various shear rates.


Evidence for water ice near Mercury's north pole from MESSENGER Neutron Spectrometer measurements.
Measurements by the Neutron Spectrometer on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft show decreases in the flux of epithermal and fast neutrons from Mercury's north polar region that are consistent with the presence of water ice in permanently shadowed regions. The neutron data indicate that Mercury's radar-bright polar deposits contain, on average, a hydrogen-rich layer more than tens of centimeters thick beneath a surficial layer 10 to 30 cm thick that is less rich in hydrogen. Combined neutron and radar data are best matched if the buried layer consists of nearly pure water ice. The upper layer contains less than 25 weight % water-equivalent hydrogen. The total mass of water at Mercury's poles is inferred to be 2 × 10(16) to 10(18) grams and is consistent with delivery by comets or volatile-rich asteroids.


Sex-dependent changes in anxiety, memory, and monoamines following one week of stress.
Chronic restraint stress alters performance of rats on cognitive tasks, and anxiety measurements, and these stress-induced behavioral alterations are sexually dimorphic. Following a long stress period (21 days restraint) males show cognitive impairments while females are either not affected or enhanced on the same tasks. The current study examined whether sexually differentiated responses are also induced following shorter restraint stress durations. Male and female Sprague Dawley rats, aged 2.5 months, served as controls or received restraint stress (6 h/day, 7 days) and were tested for anxiety (plus maze), non-spatial memory (object recognition), and spatial memory (object placement). Plus maze performance was altered by sex and stress exposure. Stress impaired male object recognition but did not affect female performance. Stress did not affect male spatial memory; however, control females could not significantly discriminate between the old and new locations, but stress exposure enhanced female performance. Following behavioral testing, monoamines and metabolites were measured in prefrontal cortex (PFC), hippocampus (CA1, CA3), and amygdala. Notably, PFC and CA3 indices for noradrenergic activity (MHPG levels and MHPG/NE ratios) were increased in stress females, but decreased in males, and similar changes were found in CA1 and BLA dopaminergic indices. Thus, these sexually dimorphic neurochemical changes following stress may underlie the behavioral differences. Current results show that short-term restraint elicits sex-dependent behavioral and neural changes different from those previously reported for longer term stresses and suggest that the temporal relationship between the change from adaptive to maladaptive responses to stress is shorter in male than female rats.


Disease-driven reduction in human mobility influences human-mosquito contacts and dengue transmission dynamics.
Heterogeneous exposure to mosquitoes determines an individual's contribution to vector-borne pathogen transmission. Particularly for dengue virus (DENV), there is a major difficulty in quantifying human-vector contacts due to the unknown coupled effect of key heterogeneities. To test the hypothesis that the reduction of human out-of-home mobility due to dengue illness will significantly influence population-level dynamics and the structure of DENV transmission chains, we extended an existing modeling framework to include social structure, disease-driven mobility reductions, and heterogeneous transmissibility from different infectious groups. Compared to a baseline model, naïve to human pre-symptomatic infectiousness and disease-driven mobility changes, a model including both parameters predicted an increase of 37% in the probability of a DENV outbreak occurring; a model including mobility change alone predicted a 15.5% increase compared to the baseline model. At the individual level, models including mobility change led to a reduction of the importance of out-of-home onward transmission (R, the fraction of secondary cases predicted to be generated by an individual) by symptomatic individuals (up to -62%) at the expense of an increase in the relevance of their home (up to +40%). An individual's positive contribution to R could be predicted by a GAM including a non-linear interaction between an individual's biting suitability and the number of mosquitoes in their home (>10 mosquitoes and 0.6 individual attractiveness significantly increased R). We conclude that the complex fabric of social relationships and differential behavioral response to dengue illness cause the fraction of symptomatic DENV infections to concentrate transmission in specific locations, whereas asymptomatic carriers (including individuals in their pre-symptomatic period) move the virus throughout the landscape. Our findings point to the difficulty of focusing vector control interventions reactively on the home of symptomatic individuals, as this approach will fail to contain virus propagation by visitors to their house and asymptomatic carriers.


Disease-toxicant screen reveals a neuroprotective interaction between Huntington's disease and manganese exposure.
Recognizing the similarities between Huntington's disease (HD) pathophysiology and the neurotoxicology of various metals, we hypothesized that they may exhibit disease-toxicant interactions revealing cellular pathways underlying neurodegeneration. Here, we utilize metals and the STHdh mouse striatal cell line model of HD to perform a gene-environment interaction screen. We report that striatal cells expressing mutant Huntingtin exhibit elevated sensitivity to cadmium toxicity and resistance to manganese toxicity. This neuroprotective gene-environment interaction with manganese is highly specific, as it does not occur with iron, copper, zinc, cobalt, cadmium, lead, or nickel ions. Analysis of the Akt cell stress signaling pathway showed diminished activation with manganese exposure and elevated activation after cadmium exposure in the mutant cells. Direct examination of intracellular manganese levels found that mutant cells have a significant impairment in manganese accumulation. Furthermore, YAC128Q mice, a HD model, showed decreased total striatal manganese levels following manganese exposure relative to wild-type mice. Thus, this disease-toxicant interaction screen has revealed that expression of mutant Huntingtin results in heightened sensitivity to cadmium neurotoxicity and a selective impairment of manganese accumulation.


EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.
The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation.


Pivotal Roles of Cryptochromes 1a and 2 in Tomato Development and Physiology.
Cryptochromes are flavin-containing blue/UVA light photoreceptors that regulate various plant light-induced physiological processes. In Arabidopsis (Arabidopsis thaliana), cryptochromes mediate de-etiolation, photoperiodic control of flowering, entrainment of the circadian clock, cotyledon opening and expansion, anthocyanin accumulation, and root growth. In tomato (Solanum lycopersicum), cryptochromes are encoded by a multigene family, comprising CRY1a, CRY1b, CRY2, and CRY3 We have previously reported the phenotypes of tomato cry1a mutants and CRY2 overexpressing plants. Here, we report the isolation by targeting induced local lesions in genomes, of a tomato cry2 knock-out mutant, its introgression in the indeterminate Moneymaker background, and the phenotypes of cry1a/cry2 single and double mutants. The cry1a/cry2 mutant showed phenotypes similar to its Arabidopsis counterpart (long hypocotyls in white and blue light), but also several additional features such as increased seed weight and internode length, enhanced hypocotyl length in red light, inhibited primary root growth under different light conditions, anticipation of flowering under long-day conditions, and alteration of the phase of circadian leaf movements. Both cry1a and cry2 control the levels of photosynthetic pigments in leaves, but cry2 has a predominant role in fruit pigmentation. Metabolites of the sterol, tocopherol, quinone, and sugar classes are differentially accumulated in cry1a and cry2 leaves and fruits. These results demonstrate a pivotal role of cryptochromes in controlling tomato development and physiology. The manipulation of these photoreceptors represents a powerful tool to influence important agronomic traits such as flowering time and fruit quality.


A combinatorial code of maternal GATA, Ets and beta-catenin-TCF transcription factors specifies and patterns the early ascidian ectoderm.
Our understanding of the maternal factors that initiate early chordate development, and of their direct zygotic targets, is still fragmentary. A molecular cascade is emerging for the mesendoderm, but less is known about the ectoderm, giving rise to epidermis and nervous tissue. Our cis-regulatory analysis surprisingly places the maternal transcription factor Ci-GATAa (GATA4/5/6) at the top of the ectodermal regulatory network in ascidians. Initially distributed throughout the embryo, Ci-GATAa activity is progressively repressed in vegetal territories by accumulating maternal beta-catenin. Once restricted to the animal hemisphere, Ci-GATAa directly activates two types of zygotic ectodermal genes. First, Ci-fog is activated from the 8-cell stage throughout the ectoderm, then Ci-otx is turned on from the 32-cell stage in neural precursors only. Whereas the enhancers of both genes contain critical and interchangeable GATA sites, their distinct patterns of activation stem from the additional presence of two Ets sites in the Ci-otx enhancer. Initially characterized as activating elements in the neural lineages, these Ets sites additionally act as repressors in non-neural lineages, and restrict GATA-mediated activation of Ci-otx. We thus identify a precise combinatorial code of maternal factors responsible for zygotic onset of a chordate ectodermal genetic program.


Folate Receptor Alpha Peptide Vaccine Generates Immunity in Breast and Ovarian Cancer Patients.
Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity, and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients.Patients and Methods: We conducted a phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low-dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to 1 year later.Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in more than 90% of patients examined. Unlike recall immunity to tetanus toxoid (TT), FR T-cell responses developed slowly over the course of vaccination with a median time to maximal immunity in 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months.Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen, and the developed vaccine is testable for therapeutic activity in most patients whose tumors express FR, regardless of HLA genotype. Clin Cancer Res; 24(13); 3014-25. ©2018 AACR.


Recovery Kinetics: Comparison of Patients Undergoing Primary or Revision Procedures for Adult Cervical Deformity Using a Novel Area Under the Curve Methodology.
Limited data are available to objectively define what constitutes a "good" versus a "bad" recovery for operative cervical deformity (CD) patients. Furthermore, the recovery patterns of primary versus revision procedures for CD is poorly understood. To define and compare the recovery profiles of CD patients undergoing primary or revision procedures, utilizing a novel area-under-the-curve normalization methodology. CD patients undergoing primary or revision surgery with baseline to 1-yr health-related quality of life (HRQL) scores were included. Clinical symptoms and HRQL were compared among groups (primary/revision). Normalized HRQL scores at baseline and follow-up intervals (3M, 6M, 1Y) were generated. Normalized HRQLs were plotted and area under the curve was calculated, generating one number describing overall recovery (Integrated Health State). Subanalysis identified recovery patterns through 2-yr follow-up. Eighty-three patients were included (45 primary, 38 revision). Age (61.3 vs 61.9), gender (F: 66.7% vs 63.2%), body mass index (27.7 vs 29.3), Charlson Comorbidity Index, frailty, and osteoporosis (20% vs 13.2%) were similar between groups (P > .05). Primary patients were more preoperatively neurologically symptomatic (55.6% vs 31.6%), less sagittally malaligned (cervical sagittal vertical axis [cSVA]: 32.6 vs 46.6; T1 slope: 28.8 vs 36.8), underwent more anterior-only approaches (28.9% vs 7.9%), and less posterior-only approaches (37.8% vs 60.5%), all P < .05. Combined approaches, decompressions, osteotomies, and construct length were similar between groups (P > .05). Revisions had longer op-times (438.0 vs 734.4 min, P = .008). Following surgery, complication rate was similar between groups (66.6% vs 65.8%, P = .569). Revision patients remained more malaligned (cSVA, TS-CL; P < .05) than primary patients until 1-yr follow-up (P > .05). Normalized HRQLs determined primary patients to exhibit less neck pain (numeric rating scale [NRS]) and myelopathy (modified Japanese Orthopaedic Association) symptoms through 1-yr follow-up compared to revision patients (P < .05). These differences subsided when following patients through 2 yr (P > .05). Despite similar 2-yr HRQL outcomes, revision patients exhibited worse neck pain (NRS) Integrated Health State recovery (P < .05). Despite both primary and revision patients exhibiting similar HRQL outcomes at final follow-up, revision patients were in a greater state of postoperative neck pain for a greater amount of time.


Proteome-transcriptome analysis and proteome remodeling in mouse lens epithelium and fibers.
Epithelial cells and differentiated fiber cells represent distinct compartments in the ocular lens. While previous studies have revealed proteins that are preferentially expressed in epithelial vs. fiber cells, a comprehensive proteomics library comparing the molecular compositions of epithelial vs. fiber cells is essential for understanding lens formation, function, disease and regenerative potential, and for efficient differentiation of pluripotent stem cells for modeling of lens development and pathology in vitro. To compare protein compositions between the lens epithelium and fibers, we employed tandem mass spectrometry (2D-LC/MS) analysis of microdissected mouse P0.5 lenses. Functional classifications of the top 525 identified proteins into gene ontology categories by molecular processes and subcellular localizations, were adapted for the lens. Expression levels of both epithelial and fiber proteomes were compared with whole lens proteome and mRNA levels using E14.5, E16.5, E18.5, and P0.5 RNA-Seq data sets. During this developmental time window, multiple complex biosynthetic and catabolic processes generate the molecular and structural foundation for lens transparency. As expected, crystallins showed a high correlation between their mRNA and protein levels. Comprehensive data analysis confirmed and/or predicted roles for transcription factors (TFs), RNA-binding proteins (e.g. Carhsp1), translational apparatus including ribosomal heterogeneity and initiation factors, microtubules, cytoskeletal [e.g. non-muscle myosin IIA heavy chain (Myh9) and βB2-spectrin (Sptbn2)] and membrane proteins in lens formation and maturation. Our data highlighted many proteins with unknown functions in the lens that were preferentially enriched in epithelium or fibers, setting the stage for future studies to further dissect the roles of these proteins in fiber cell differentiation vs. epithelial cell maintenance. In conclusion, the present proteomic datasets represent the first mouse lens epithelium and fiber cell proteomes, establish comparative analyses of protein and RNA-Seq data, and characterize the major proteome remodeling required to form the mature lens fiber cells.


Understanding the uptake of family-based treatment for adolescents with anorexia nervosa: therapist perspectives.
To explore and describe therapists' perceptions of the factors affecting their uptake of family-based treatment (FBT) for adolescents with anorexia nervosa (AN). Fundamental qualitative description guided the sampling and data collection in this study. A purposeful sample of 40 therapists providing treatment to youth with AN, completed an in-depth interview. Conventional content analysis guided the development of initial codes and categories, whereas constant comparison analytic techniques were used to compare and contrast therapist perceptions across contexts. Summative content analysis was used to provide counts of keywords, phrases, and themes. Therapists face several barriers to the implementation of FBT, divided broadly into interventional, organizational, interpersonal, patient/family, systemic, and illness factors. Therapists support the implementation of evidence-based practices, including FBT for AN, but fidelity to this model is not practiced. Specific concerns about the intervention included weighing the patient, providing nutritional advice, and the family meal. Ninety-five percent of therapists requested further training in the FBT model. Further investigation into the barriers and facilitating factors to the use of FBT is warranted. Understanding effective dissemination and training strategies is critical to ensuring patients receive the best possible care.


Blood pressure and serum cholesterol among male Ethiopian immigrants compared to other Israelis.
The aim was to determine the effect of migration from a non-industrialised to an industrialised society on age related changes in blood pressure and serum cholesterol. The study was a comparison of major risk factors for cardiovascular disease in cross sectional surveys in two groups: Ethiopian immigrants and Israeli industrial employees. Ethiopian immigrants were examined at Army induction centres in Israel; industrial employees were examined in the course of a national Israeli study on occupational risk factors for cardiovascular disease. Participants were a sample of 387 male Ethiopians, aged 20-49 years, examined in 1987, who had immigrated to Israel three to four years previously, and a sample of 2747 male Israeli industrial employees in the same age group examined in 1985-7. Among the Ethiopians there were no cases of overweight (Quetelet's index above 2.8) and only 6.7% were smokers, as compared with 20.7% overweight and 47.1% smokers among the other Israelis (p less than 0.001 for both variables). There were no significant differences in the prevalence of hypertension (11.6% and 13.0% for Ethiopians and other Israelis respectively). Hypercholesterolaemia (greater than 5.2 mmol/litre, 200 mg/dl) was much more prevalent among the other Israelis (42.0% v 9.6%, p less than 0.001). Blood pressures were similar and increased with age in both groups. However, in contrast to the other Israelis, average serum cholesterol among the Ethiopians was low and increased minimally with age. After regression adjustment for age and body mass index, blood pressures were higher among the Ethiopians, whereas serum cholesterol remained considerably higher among the other Israelis. Serum cholesterol was correlated with blood pressure in both groups. Since Ethiopian immigrants have been found to have uniformly low blood pressures on arrival in Israel, these findings suggest that there is an age dependent effect on blood pressure resulting from migration which is not reflected in the serum cholesterol values.


Health technology identities and self. Patients' appropriation of an assistive device for self-management of chronic illness.
In recent years, assistive technologies have gained acceptance as tools for supporting chronically ill patients in achieving improvements in physical activity. However, various healthcare and sociological studies show contradicting results regarding the physical and social impact of using such devices. This paper explores real-time user appropriation of an assistive monitoring/tracking device, the pedometer, in a healthcare intervention, with a particular focus on the technology identities users attribute to the pedometer. The study site was a rehabilitation programme at a local Danish health centre supporting patients with chronic obstructive pulmonary disease. As part of this empirical study, six focus-group interviews were conducted with patients before and after they used pedometers. The analysis of respondents' accounts shows that monitoring devices become part of users' complex socio-technical ensembles in which the use of the device and its tracking of activity is constantly negotiated through experimentation with type and frequency of use; interpretation of knowledge and experience gained via the device; and negotiation of expectations, wellbeing, and the value of quantified knowledge for the management of chronic illness. On the basis of these findings the paper brings together and advances sociological scholarship on chronic illness, embodiment, the quantified self and technology adoption.


"It isn't just consultants that need a BSc": student experiences of an Intercalated BSc in primary health care.
More medical schools are moving towards a compulsory intercalated BSc. These courses have not traditionally been aimed at those students interested in general practice and have tended to have limited clinical relevance. This paper explores the perceptions of students who undertook a BSc in primary health care using qualitative methodology comprising semi-structured interviews with students just before completion of their course. Interviews were undertaken with 24 of the 26 students who started the course over a 4-year period. All the students have finished the course and have graduated with good honours degrees. Students refine existing skills and develop new, relevant skills for medicine. The students discussed the prestige (or lack) of a BSc in this field and how the course has impacted on their career decisions. A Primary Health Care BSc such as this appears to give students an in depth and to some, a positive view of general practice and primary care. The course allowed students to develop a more critical approach to medicine and enabled them to develop skills in addition to those acquired from their undergraduate medicine course. They perceived that these skills will serve them throughout their career in whatever branch of medicine they choose.


Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study.
Studies of Australian infants have reported that more than 80% of those with moderate atopic eczema (AE) have high levels of IgE food sensitization (IgE-FS) that are commonly associated with IgE food allergy. To explore the relationship between high levels of IgE-FS and AE in a large cohort of young children with eczema participating in a multi-centre, international study. Two thousand one hundred and eighty-four subjects (mean age 17.6 months, range 11.8-25.4; 1246 males) with active eczema from atopic families from 94 centres in 12 countries were studied. Clinical history, Scoring Atopic Dermatitis index as a measure of eczema severity and CAP-FEIA measurements for total IgE and IgE antibody levels to cow milk, egg and peanut were entered into a database. If CAP-FEIA levels exceeded previously reported age-specific cut-off levels for 95% positive predictive values (PPVs) for food allergy, subjects were defined as having high-risk IgE-FS (HR-IgE-FS). Serum was available from 2048 patients; 55.5% were atopic. The frequency of HR-IgE-FS to milk, egg and/or peanut was the greatest in patients whose eczema developed in the first 3 months of life and the least in those whose eczema developed after 12 months (P<0.0001). In a regression analysis to allow for potential confounding factors, children with HR-IgE-FS had the most severe eczema and the youngest age of onset (P<0.001); 64% of infants with severe eczema of onset-age <3 months had HR-IgE-FS. Early-onset severe eczema in infancy was associated with HR-IgE-FS. Clinical implications Food allergies should be routinely assessed in infants with moderate or severe eczema. Capsule summary In eczematous infants, the earlier the age of onset, and the greater the severity of eczema, the greater the frequency of associated high levels of IgE-FS.


Use of confocal imaging in the study of biological structures.
Scanning confocal microscopy offers several potential advantages for light microscope studies of biological material. Foremost amongst these is the rejection of interfering signals from out-of-focus structures, which often seriously degrade images. The degradation in image quality with epifluorescence microscopy is particularly pronounced; an unfortunate situation, as this is one of the most commonly used techniques in biological research. Confocal imaging almost completely eliminates this problem and therefore promises to have a wide application in this area. We have developed a high-speed beam scanning confocal imaging system that can be used in conjunction with a conventional microscope, and have examined a variety of biological material using this system. In all cases we have found that confocal imaging gives a marked improvement in quality over conventional techniques. viewed with epifluorescence.


Using Food and Nutritional Strategies to Induce Tolerance in Food-Allergic Children.
Food allergy is an important and increasing public health problem worldwide, affecting predominantly infants and young children. There is an urgent need to develop effective treatment strategies to restore oral tolerance in food-allergic individuals. Among diverse research approaches, those involving native or heat-modified food proteins are most advanced and are currently being evaluated in clinical trials. Extensively heated (baked) milk and egg diets have already been adopted in clinical practice and benefit the majority of milk- and egg-allergic children. Oral, sublingual and epicutaneous immunotherapy with native foods remain in the sphere of clinical research with encouraging data suggesting that they may induce desensitization in a large proportion of treated patients and potentially permanent tolerance following an adequately long period of treatment. Synbiotics appear to have the most beneficial role in the prevention of food allergy; Lactobacillus rhamnosus GG may promote the development of tolerance to milk in allergic infants.


Altered prostacyclin synthesis by aortae from hepatic portal vein-constricted rats: evidence for effects on protein kinase C and calcium.
To investigate the mechanisms causing reduced systemic vascular reactivity to vasoconstrictor agents in portal hypertension, we studied receptor- and signal-transduction-linked PGI2 (a vasodilator) synthesis (measured as 6-oxo-PGF1 alpha by radioimmunoassay) in the aorta (ex vivo) of portal vein-constricted rats. PGI2 synthesis was stimulated by adrenaline (via heterogeneous alpha-adrenoceptors), phorbol ester dibutyrate (a protein kinase C activator), arachidonic acid (the substrate for PGI2 synthesis) and the Ca2+ ionophore A23187 (A23187) and thapsigargin (both of which elevate intracellular Ca2+, which in turn elicits the release of arachidonic acid). The release of PGI2 by the aortae of rats with portal hypertension in comparison to sham-operated controls was: 1) enhanced in response to adrenaline, 2) reduced in response to phorbol ester dibutyrate, A23187 and thapsigargin and 3) unchanged in response to arichidonic acid. These data indicate that in aortae from rats with experimental portal hypertension: i) there are no changes in the enzymes involved in PGI2 synthesis (cyclooxygenase, PGI2 synthase), ii) there is a specific increase in adrenoceptor-linked PGI2 synthesis in aortae which may contribute to arterial vasodilation in this experimental model and 3) the diminished response of PGI2 synthesis to A23187, phorbol ester dibutyrate and thapsigargin indicates that there is a generalised attenuation of protein kinase C activator activity and of Ca2+. Since Ca2+ is a key component of excitation-contraction coupling and protein kinase C activator has been implicated in mediating this event, attenuation of these systems may also explain, at least in part, the known reduced vasoactivity of aortae from rats with portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)


Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods.
The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)-a benzodiazepine exerting an agonist action on GABAA receptors-may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.


Effect of Rhazya stricta on the developing rat fetus.
Rhazya stricta is a medicinal plant traditionally used in the treatment of diabetes mellitus, inflammation, and helminthiasis. Our objective was to determine if the plant extract has any effect on fetal development in the rat. A lyophilized extract of the plant was administered daily on three consecutive gestation days (GD) covering the period of preimplantation and organogenesis. The fetuses were examined on GD 20. Higher doses (5.0 or 8.0 g/kg) of R. stricta generally caused a reduction in maternal weight gain, compared to controls, whereas the lower doses (0.5 to 2.0 g/kg) did not. Treatment on GD 1, 2, 3, or 7, 8, 9 had no effect on the fetal weight. Treatment on later days GD 8, 9, 10, or 10, 11, 12, or 13, 14, 15 reduced both the number of live fetuses and their weight. Pronounced intrauterine growth retardation (IUGR) was observed in groups treated at later stages, particularly in the high dose groups. Extreme resorption characterized R. stricta treatment on GD 10, 11, and 12. Examination of the conceptus 24 h after R. stricta treatment indicated retarded placental development associated with hypovascularity, which possibly contributed to the IUGR and fetal death. The incidence of malformations such as micromelia, adactyly, maxillary-mandibular hypoplasia, protruding tongue, and edema, did not reach statistical significance. Except perhaps for a generalized growth retardation, no skeletal malformations were obvious. These observations are suggestive of potential fetal toxicity of R. stricta if taken during pregnancy.


Relating brain signal variability to knowledge representation.
We assessed the hypothesis that brain signal variability is a reflection of functional network reconfiguration during memory processing. In the present experiments, we use multiscale entropy to capture the variability of human electroencephalogram (EEG) while manipulating the knowledge representation associated with faces stored in memory. Across two experiments, we observed increased variability as a function of greater knowledge representation. In Experiment 1, individuals with greater familiarity for a group of famous faces displayed more brain signal variability. In Experiment 2, brain signal variability increased with learning after multiple experimental exposures to previously unfamiliar faces. The results demonstrate that variability increases with face familiarity; cognitive processes during the perception of familiar stimuli may engage a broader network of regions, which manifests as higher complexity/variability in spatial and temporal domains. In addition, effects of repetition suppression on brain signal variability were observed, and the pattern of results is consistent with a selectivity model of neural adaptation.


Impact of schoolchildren's involvement in the design process on the effectiveness of healthy food promotion materials.
Marketing techniques may improve children's vegetable consumption. However, student participation in the design of marketing materials may increase the material's salience, while also improving children's commitment and attitudes towards healthy eating. The impact of student-led design of vegetable promotional materials on choice and consumption was investigated using 1614 observations of students' vegetable choice and plate waste in four public elementary schools in Kearney, Nebraska. Data were collected on children's vegetable choice and consumption in four comparison groups: 1) control; 2) students designed materials only; 3) students were exposed to promotional materials only; and 4) students designed materials that were then posted in the lunchroom. Vegetable choice and consumption data were collected through a validated digital photography-based plate-waste method. Multivariate linear regression was used to estimate average treatment effects of the conditions at various time periods. Dependent variables were vegetable choice and consumption, and independent variables included the condition, time period, and interaction terms, as well as controls for gender and grade. Relative to baseline, students in group 4 doubled their vegetable consumption (p < 0.001) when materials were posted. Vegetable consumption remained elevated at a follow-up 2-3 months later (p < 0.05). Students in group 3 initially increased the quantity of vegetables selected (p < 0.05), but did not increase consumption. In the follow-up period, however, students in group 3 increased their vegetable consumption (p < 0.01). Involving elementary-aged students in the design of vegetable promotional materials that were posted in the lunchroom increased the amount of vegetables students consumed.


An anther-specific gene encoded by an S locus haplotype of Brassica produces complementary and differentially regulated transcripts.
The self-incompatibility locus of Brassica consists of a coadapted gene complex that contains at least two genes required for the recognition and inhibition of pollen by the stigma when self-pollinated. Here, we report the identification of a third S locus-linked gene from the S2 haplotype of Brassica oleracea. This gene, which we designated SLA (for S Locus Anther), is a novel gene with an unusual structure. SLA is transcribed from two promoters to produce two complementary anther-specific transcripts, one spliced and the other unspliced, that accumulate in an antiparallel manner in developing microspores and anthers. The sequence of the spliced transcript showed the presence of two open reading frames that predict proteins of 10 and 7.5 kD. Neither transcript was produced in a self-compatible B. napus strain carrying an S2-like haplotype, indicating that the SLA gene in this strain is nonfunctional. Interestingly, sequences related to SLA were not detected in DNA or RNA from plants carrying S haplotypes other than S2. The haplotype specificity of SLA, its anther-specific expression, and its physical linkage to the S locus are properties expected for a gene that encodes a determinant of S2 specificity in pollen.


Enhancing the visual realism of hysteroscopy simulation.
Visualization is a very important part of a high fidelity surgical simulator. Due to modern computer graphics hardware, which offers more and more features and processing power, it is possible to extend the standard OpenGL rendering methods with advanced visualization techniques to achieve highly realistic rendering in real-time. For an easy and efficient use of these new capabilities, a stand-alone graphics engine has been implemented, which exploits these advanced rendering techniques and provides an interface in order to ensure the interoperability with a software framework for surgical simulators.


Understanding and Overcoming the Sticking Point in Resistance Exercise.
In the context of resistance training the so-called "sticking point" is commonly understood as the position in a lift in which a disproportionately large increase in the difficulty to continue the lift is experienced. If the lift is taken to the point of momentary muscular failure, the sticking point is usually where the failure occurs. Hence the sticking point is associated with an increased chance of exercise form deterioration or breakdown. Understanding the mechanisms that lead to the occurrence of sticking points as well as different training strategies that can be used to overcome them is important to strength practitioners (trainees and coaches alike) and instrumental for the avoidance of injury and continued progress. In this article we survey and consolidate the body of existing research on the topic: we discuss different definitions of the sticking point adopted in the literature and propose a more precise definition, describe different muscular and biomechanical aspects that give rise to sticking points, and review the effectiveness of different training modalities used to address them.


Clostridium difficile infections before and during use of ultraviolet disinfection.
We previously reported a significant decrease in hospital-acquired (HA) Clostridium difficile infection (CDI) coincident with the introduction of pulsed xenon ultraviolet light for room disinfection (UVD). The purpose of this study was to evaluate CDI cases in greater detail to understand the effect of UVD. CDI rates (HA and community acquired [CA]), CDI patient length of stay, room occupancy, and number of days between a CDI case in a room and an HA CDI case in the same room were studied for the first year of UVD compared with the 1-year period pre-UVD. Compared with pre-UVD, during UVD, HA CDI was 22% less (P = .06). There was a 70% decrease for the adult intensive care units (ICUs) (P < .001), where the percentage of room discharges with UVD was greater (P < .001). During UVD, CA CDI increased by 18%, and length of stay of all CDI cases was lower because of the greater proportion of CA CDI. No significant difference was found in days to HA CDI in rooms with a prior CDI occupant. These data suggest that UVD contributed to a reduction in ICU-acquired CDI where UVD was used for a larger proportion of discharges. Evaluation of UVD should include data for hospitalized CA CDI cases because these cases may impact the HA CDI rate.


[Factors associated with pulmonary disease among the elderly].
To investigate the prevalence of reported pulmonary disease among elderly subjects, according to sociodemographic and economic characteristics, lifestyle, physical mobility, and health status. This was a cross-sectional population-based study that included 1,957 elderly subjects (aged 60 and over). Information was collected by means of interviews. Subjects were selected using a two-stage probabilistic, stratified, cluster sampling strategy in six municipalities in the State of São Paulo between 2001 and 2002. Descriptive statistics, chi-squared association tests, prevalence ratios, and 95% confidence intervals were utilized. Adjusted analysis was carried out by Poisson regression. Among the interviewees, around 7% reported pulmonary disease. There was no association between pulmonary disease and influenza vaccination. Adjusted analysis identified the following factors that were independently associated with reported disease: smoking (PR: 2.03; 95% CI: 1.39-2.97); medication use (PR: 2.05; 95% CI: 1.11-3.79); health status self-assessed as poor or very poor (PR: 1.89; 95% CI: 1.20-2.96); and depression, anxiety, or emotional problems (PR: 1.86; 95% CI: 1.11-3.10). The findings from the present study reinforce the importance of respiratory diseases among the elderly, particularly in more vulnerable groups. Preventive measures and specific care for such groups are therefore justified.


Color opponent receptive fields self-organize in a biophysical model of visual cortex via spike-timing dependent plasticity.
Although many computational models have been proposed to explain orientation maps in primary visual cortex (V1), it is not yet known how similar clusters of color-selective neurons in macaque V1/V2 are connected and develop. In this work, we address the problem of understanding the cortical processing of color information with a possible mechanism of the development of the patchy distribution of color selectivity via computational modeling. Each color input is decomposed into a red, green, and blue representation and transmitted to the visual cortex via a simulated optic nerve in a luminance channel and red-green and blue-yellow opponent color channels. Our model of the early visual system consists of multiple topographically-arranged layers of excitatory and inhibitory neurons, with sparse intra-layer connectivity and feed-forward connectivity between layers. Layers are arranged based on anatomy of early visual pathways, and include a retina, lateral geniculate nucleus, and layered neocortex. Each neuron in the V1 output layer makes synaptic connections to neighboring neurons and receives the three types of signals in the different channels from the corresponding photoreceptor position. Synaptic weights are randomized and learned using spike-timing-dependent plasticity (STDP). After training with natural images, the neurons display heightened sensitivity to specific colors. Information-theoretic analysis reveals mutual information between particular stimuli and responses, and that the information reaches a maximum with fewer neurons in the higher layers, indicating that estimations of the input colors can be done using the output of fewer cells in the later stages of cortical processing. In addition, cells with similar color receptive fields form clusters. Analysis of spiking activity reveals increased firing synchrony between neurons when particular color inputs are presented or removed (ON-cell/OFF-cell).


Stress amongst nurses working in a healthcare telephone-advice service: relationship with job satisfaction, intention to leave, sickness absence, and performance.
This paper is a report of a study, which assessed levels of stress amongst nurses working in a healthcare telephone-advice service. We explored whether stress related to performance, sickness absence, and intention to leave. Nurses report high levels of stress, as do call-centre workers. The emergence of telephone health advice services means many nurses now work in call-centres, doing work that differs markedly from traditional nursing roles. Stress associated with these roles could have implications for nurses, patients, and service provision. This paper reports cross-sectional survey results. The design of the overall study included longitudinal elements. A comprehensive study of stress was conducted amongst nurses working for a telephone-advice service in Scotland (2008-2010). All nurse-advisors were approached by letter and invited to participate. A total of 152 participants (33%) completed a questionnaire including General Health Questionnaire-12, Work Family Conflict Questionnaire, Job Satisfaction Scale and a measure of intention to leave the telephone-advice service and rated the perceived stress of 2 working shifts. Nurses' employers provided data on sickness absence and performance. Overall levels of psychological distress were similar to those found amongst Scottish women generally. In multiple regression, work-family conflict was identified as a significant predictor of job satisfaction and intention to leave, and significantly related to sickness absence. There were significant correlations between General Health Questionnaire scores and perceived stress of shifts and some performance measures. Work-family conflict is a significant predictor of job satisfaction, intention to leave, and sickness absence amongst telephone helpline nurses. Minimizing the impact of nurses' work on their home lives might reduce turnover and sickness absence.


Production of stem cells with embryonic characteristics from human umbilical cord blood.
When will embryonic stem cells reach the clinic? The answer is simple -- not soon! To produce large quantities of homogeneous tissue for transplantation, without feeder layers, and with the appropriate recipient's immunological phenotype, is a significant scientific hindrance, although adult stem (ADS) cells provide an alternative, more ethically acceptable, source. The annual global 100 million human birth rate proposes umbilical cord blood (UCB) as the largest untouched stem cell source, with advantages of naive immune status and relatively unshortened telomere length. Here, we report the world's first reproducible production of cells expressing embryonic stem cell markers, - cord-blood-derived embryonic-like stem cells (CBEs). UCB, after elective birth by Caesarean section, has been separated by sequential immunomagnetic removal of nucleate granulocytes, erythrocytes and haemopoietic myeloid/lymphoid progenitors. After 7 days of high density culture in microflasks, (10(5) cells/ml, IMDM, FCS 10%, thrombopoietin 10 ng/ml, flt3-ligand 50 ng/ml, c-kit ligand 20 ng/ml). CBE colonies formed adherent to the substrata; these were maintained for 6 weeks, then were subcultured and continued for a minimum 13 weeks. CBEs were positive for TRA-1-60, TRA-1-81, SSEA-4, SSEA-3 and Oct-4, but not SSEA-1, indicative of restriction in the human stem cell compartment. The CBEs were also microgravity--bioreactor cultured with hepatocyte growth medium (IMDM, FCS 10%, HGF 20 ng/ml, bFGF 10 ng/ml, EGF 10 ng/ml, c-kit ligand 10 ng/ml). After 4 weeks the cells were found to express characteristic hepatic markers, cytokeratin-18, alpha-foetoprotein and albumin. Thus, such CBEs are a viable human alternative from embryonic stem cells for stem cell research, without ethical constraint and with potential for clinical applications.


Cortical thickness in ALS: towards a marker for upper motor neuron involvement.
Examine whether cortical thinning is a disease-specific phenomenon across the spectrum of motor neuron diseases in relation to upper motor neuron (UMN) involvement. 153 patients (112 amyotrophic lateral sclerosis (ALS), 19 patients with a clinical UMN phenotype, 22 with a lower motor neuron (LMN) phenotype), 60 healthy controls and 43 patients with an ALS mimic disorder were included for a cross-sectional cortical thickness analysis. Thirty-nine patients with ALS underwent a follow-up scan. T1-weighted images of the brain were acquired using a 3 T scanner. The relation between cortical thickness and clinical measures, and the longitudinal changes were examined. Cortical thickness of the precentral gyrus (PCG) was significantly reduced in ALS (p=1.71×10(-13)) but not in mimic disorders (p=0.37) or patients with an LMN phenotype (p=0.37), as compared to the group of healthy controls. Compared to patients with ALS, patients with a UMN phenotype showed an even lower PCG cortical thickness (p=1.97×10(-3)). Bulbar scores and arm functional scores showed a significant association with cortical thickness of corresponding body regions of the motor homunculus. Longitudinal analysis revealed a decrease of cortical thickness in the left temporal lobe of patients with ALS (parahippocampal region p=0.007 and fusiform cortex p=0.001). PCG cortical thinning was found to be specific for motor neuron disease with clinical UMN involvement. Normal levels of cortical thickness in mimic disorders or LMN phenotypes suggest that cortical thinning reflects pathological changes related to UMN involvement. Progressive cortical thinning in the temporal lobe suggests recruitment of non-motor areas, over time.


Pregnancy associated breast cancer.
Breast carcinoma during pregnancy put the health of the mother in conflict with that of the foetus. The aim is to give optimal treatment to the mother to maximise the chances of survival, whilst minimising the risk of harm of the foetus. We report the epidemiology, pathology, clinical picture, therapeutic management and foetal outcome of pregnant women with breast cancer treated in our institution. Twenty-two pregnant breast cancer patients were treated in our hospital from January 1996 to October 2006. Parents were surveyed by mail or telephone regarding outcomes of children exposed to chemotherapy in uterus. The treatment of breast cancer pregnancy should conform as closely as possible to standardised protocols for patients without concomitant pregnancy. Most of the patients underwent surgery during pregnancy In four cases diagnosed during the first trimester chemotherapy was initiated during the 10th week when organogenesis period was finished. None of the children exposed to chemotherapy during this trimester presented congenital malformations. All 11 cases diagnosed during second and third trimester were treated with Doxorrubicin, Fluoracil and Cyclophosphamide and four cases were treated with taxanes. No congenital malformations were detected. Breast cancer can be treated with FAC chemotherapy during the second and third trimesters without significant complications for the children exposed to chemotherapy in uterus. We report four cases treated with taxanes after the first trimester and no congenital anomalies were observed.


Cell-cell transmission enables HIV-1 to evade inhibition by potent CD4bs directed antibodies.
HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs) and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs) directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo.


Continuous versus extended antipsychotic dosing in schizophrenia: Less is more.
Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but-past acute phase treatment-it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects.


A retrospective cohort study in severe asthma describing commonly measured biomarkers: Eosinophil count and IgE levels.
Identifying asthma patients suitable for biologic therapy includes the assessment of blood biomarkers (IgE and eosinophils (EOS)). How they relate to each other is unclear. This retrospective, database study used routinely collected clinical data to identify and evaluate an asthma cohort (classification code for asthma; ≥ 18 years; ≥1 prescription for asthma; ≥1 estimation of serum IgE, in 2 years prior to index date). Distribution into high and low IgE and EOS groups (IgE cut-point: > or ≤75 kU/L; EOS cut point: >or ≤400 μ/L), and characteristics by group are described. In patients with severe asthma (British Thoracic Society Step (BTS) ≥4; N = 884), using maximum recorded IgE/EOS, 33% had high IgE/high EOS, 28% low IgE/low EOS and approximately a fifth each had high IgE/low EOS or low IgE/high EOS. Proportions were similar when EOS values measured 2 or 4 weeks before an exacerbation were excluded. Using EOS/IgE 'same day' measurements (N = 578) only identified half of the high EOS group. Patients in high IgE groups were more likely to be younger males without comorbid COPD; those in high EOS groups were more likely to be on BTS treatment Step 5 vs 4. The low IgE/low EOS group had the lowest incidence of asthma-related hospital attendances, the highest incidence was observed in the high EOS groups. Maximum available EOS measurement irrespective of exacerbations may be relevant when considering therapy. These data showed low IgE/Low EOS to be more benign and high EOS groups at increased risk of frequent, severe exacerbations.